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Entry
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- *176876 - PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*176876</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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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/176876">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000179295;t=ENST00000351677" 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=5781" 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=176876" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000179295;t=ENST00000351677" 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_001330437,NM_001374625,NM_002834,NM_080601,XM_011538613" 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_002834" 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=176876" 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=01470&isoform_id=01470_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/PTPN11" 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/35784,292407,338082,4519425,13242862,14250501,18375644,19263908,21410183,30583051,33356177,119618417,119618418,158260731,189053276,189909137,189909139,189909141,767974975,1059433492,1757649834,1786505119,1810957874,1810957876,1810957878,1810957880,1810957882,1810957884,1810957886,1810957888,1810957890,1810957892,1810957894,1810957896,1810957898,1810957900,1810957902,1810957904,1810957906,1810957908,1810957910,1810957912,1810957914,1810957916,1810957918,1810957920,1810957922,1810957924,1810957926,1810957928,1810957930,1810957932,1810957934,1810957936,1810957938,1810957940,1810957942,1810957944,1810957946,1810957948,1810957950,1810957952,1810957954,1810957956,1810957958,1810957960,1810957962,1810957964,1810957966,1810957968,1810957970,1810957972,1810957974,1810957976,1810957978,1810957982,1810957984,1810957986,1810957988,1810957990,1810957992,1810957994,1810957996,1810957998,1810958000,1810958002,1810958004,1810958006,1810958008,1810958010,1810958012,1810958014,1810958016,1810958018,1810958020,1810958022,1810958024,1810958026,1810958028,1810958030,1810958032,1810958034,1810958036,1810958038,1810958040,1810958042,1810958044,1810958046,1810958048,1810958050,1810958052,1810958054,1810958056,1810958058,1810958060,1810958062,1810958064,1810958066,1810958068,1810958070,1810958072,1810958074,1810958076,1810958078,1810958080,1810958082,1810958084,1810958086,2462533343" 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/Q06124" 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=5781" 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=ENSG00000179295;t=ENST00000351677" 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=PTPN11" 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=PTPN11" 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+5781" 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/PTPN11" 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:5781" 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/5781" 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=chr12&hgg_gene=ENST00000351677.7&hgg_start=112418947&hgg_end=112509918&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9644" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9644" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176876[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=176876[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/PTPN11/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/ENSG00000179295" 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=PTPN11" 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=PTPN11" 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=PTPN11" 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=PTPN11&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/PA33986" 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:9644" 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/FBgn0000382.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:99511" 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/PTPN11#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:99511" 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/5781/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=5781" 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=WBGene00004214;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-030131-5911" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5781" 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=PTPN11&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> 205481009, 205684007, 205824006<br />
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<strong>ICD10CM:</strong> Q87.19<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
176876
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
|
<span class="mim-font">
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PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PROTEIN-TYROSINE PHOSPHATASE 2C; PTP2C<br />
|
|
TYROSINE PHOSPHATASE SHP2; SHP2
|
|
</span>
|
|
</h4>
|
|
</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>
|
|
<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=PTPN11" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PTPN11</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/823?start=-3&limit=10&highlight=823">12q24.13</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:112418947-112509918&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'})">12:112,418,947-112,509,918</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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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>
|
|
<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">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=151100,607785,156250,163950" 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="4">
|
|
<span class="mim-font">
|
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<a href="/geneMap/12/823?start=-3&limit=10&highlight=823">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<a href="/entry/163950"> 163950 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/176876" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The protein-tyrosine phosphatases are a highly pleomorphic set of molecules that have a role in regulating the responses of eukaryotic cells to extracellular signals (<a href="#13" class="mim-tip-reference" title="Dechert, U., Duncan, A. M. V., Bastien, L., Duff, C., Adam, M., Jirik, F. R. <strong>Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3.</strong> Hum. Genet. 96: 609-615, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530013</a>] [<a href="https://doi.org/10.1007/BF00197421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530013">Dechert et al., 1995</a>). They achieve this by regulating the phosphotyrosine content of specific intracellular proteins. The PTPases have been grouped by virtue of the characteristic catalytic domain sequence similarities that define this family. <a href="#13" class="mim-tip-reference" title="Dechert, U., Duncan, A. M. V., Bastien, L., Duff, C., Adam, M., Jirik, F. R. <strong>Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3.</strong> Hum. Genet. 96: 609-615, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530013</a>] [<a href="https://doi.org/10.1007/BF00197421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530013">Dechert et al. (1995)</a> noted that the noncatalytic domain shows a striking degree of sequence heterogeneity. In general, however, mammalian PTPases can be subdivided into 1 of 2 broad categories: (1) transmembrane receptor PTPases that contain linked cytoplasmic catalytic domains, and (2) intracellular PTPases. Included within the latter category are 2 closely related mammalian intracellular PTPases whose sequences encode 2 tandem SRC homology 2 (SH2) domains that are located at the amino-terminal side of a single PTPase catalytic domain. SH2 domains enable the binding of these SH2 domain-containing PTPases to specific phosphotyrosine residues within protein sequences. The first mammalian SH2 domain-containing PTPase identified was PTP1C (PTPN6; <a href="/entry/176883">176883</a>). The second mammalian SH2 domain-containing PTPase identified is encoded by the PTPN11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8530013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Ahmad, S., Banville, D., Zhao, Z., Fischer, E. H., Shen, S.-H. <strong>A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.</strong> Proc. Nat. Acad. Sci. 90: 2197-2201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7681589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7681589</a>] [<a href="https://doi.org/10.1073/pnas.90.6.2197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7681589">Ahmad et al. (1993)</a> isolated a cDNA encoding a nontransmembrane protein-tyrosine phosphatase (PTP; <a href="https://enzyme.expasy.org/EC/3.1.3.48" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.1.3.48</a>), termed PTP2C, from a human umbilical cord cDNA library. The open reading frame consists of 1,779 nucleotides potentially encoding a protein of 593 amino acids with a predicted molecular mass of 68 kD. The identity between the 2 SH2 domains of PTP2C (PTPN11) and PTP1C (PTPN6) is 50 to 60%, higher than the identity between the 2 SH2 domains within the same molecule. Unlike PTP1C, which is restricted to hematopoietic and epithelial cells, PTP2C is widely expressed in human tissues and is particularly abundant in heart, brain, and skeletal muscle. <a href="#1" class="mim-tip-reference" title="Ahmad, S., Banville, D., Zhao, Z., Fischer, E. H., Shen, S.-H. <strong>A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.</strong> Proc. Nat. Acad. Sci. 90: 2197-2201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7681589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7681589</a>] [<a href="https://doi.org/10.1073/pnas.90.6.2197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7681589">Ahmad et al. (1993)</a> also identified a variant of PTP2C, termed PTP2Ci by them, which had an in-frame insertion of 12 basepairs within the catalytic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7681589" 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>By fluorescence in situ hybridization, <a href="#23" class="mim-tip-reference" title="Isobe, M., Hinoda, Y., Imai, K., Adachi, M. <strong>Chromosomal localization of an SH2 containing tyrosine phosphatase (SH-PTP3) gene to chromosome 12q24.1.</strong> Oncogene 9: 1751-1753, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8183573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8183573</a>]" pmid="8183573">Isobe et al. (1994)</a> mapped the PTP2C gene to 12q24.1. It is noteworthy that the PTP1C gene maps to the short arm of chromosome 12, whereas PTP2C maps to the long arm. <a href="#13" class="mim-tip-reference" title="Dechert, U., Duncan, A. M. V., Bastien, L., Duff, C., Adam, M., Jirik, F. R. <strong>Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3.</strong> Hum. Genet. 96: 609-615, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530013</a>] [<a href="https://doi.org/10.1007/BF00197421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530013">Dechert et al. (1995)</a> used a 2.1-kb SH-PTP2 cDNA clone (<a href="#3" class="mim-tip-reference" title="Bastien, L., Ramachandran, C., Liu, S., Adam, M. <strong>Cloning, expression, and mutational analysis of SH-PTP2, human protein-tyrosine phosphatase 2-domains.</strong> Biochem. Biophys. Res. Commun. 196: 124-133, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8216283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8216283</a>] [<a href="https://doi.org/10.1006/bbrc.1993.2224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8216283">Bastien et al., 1993</a>) to localize the PTPN11 gene to 12q24.1-q24.3 by isotopic in situ hybridization. The presence of cross-hybridizing sequences located on a number of other chromosomes suggested that latent genes or pseudogenes are present in the human genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8183573+8530013+8216283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#21" class="mim-tip-reference" title="Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J., Shoelson, S. E. <strong>Crystal structure of the tyrosine phosphatase SHP-2.</strong> Cell 92: 441-450, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9491886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9491886</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80938-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9491886">Hof et al. (1998)</a> described the crystal structure of amino acid residues 1 to 527 of the PTPN11 protein at 2.0-angstrom resolution. The crystal structure showed how its catalytic activity is regulated by its two SH2 domains. In the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain binds the phosphatase domain and directly blocks its active site. This interaction alters the structure of the N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely, interaction of the N-SH2 domain with phosphopeptide disrupts its phosphatase recognition surface. Thus, the N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-terminal SH2 domain contributes binding energy and specificity, but does not have a direct role in activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9491886" 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>Reduction of SHP2 activity suppresses tumor cell growth and is a potential target of cancer therapy. <a href="#11" class="mim-tip-reference" title="Chen, Y.-N. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcia-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H.-T., Chen, Z., Cooke, V. G., Dobson, J. R., Deng, Z., and 41 others. <strong>Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.</strong> Nature 535: 148-152, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27362227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27362227</a>] [<a href="https://doi.org/10.1038/nature18621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27362227">Chen et al. (2016)</a> reported the discovery of a highly potent (IC50 = 0.071 micromolar), selective, and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an autoinhibited conformation. The crystal structure of SHP099 in complex with to SHP2 at 1.7-angstrom resolution showed that SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppressed RAS-ERK signaling to inhibit the proliferation of receptor tyrosine kinase-driven human cancer cells in vitro and was efficacious in mouse tumor xenograft models. <a href="#11" class="mim-tip-reference" title="Chen, Y.-N. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcia-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H.-T., Chen, Z., Cooke, V. G., Dobson, J. R., Deng, Z., and 41 others. <strong>Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.</strong> Nature 535: 148-152, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27362227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27362227</a>] [<a href="https://doi.org/10.1038/nature18621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27362227">Chen et al. (2016)</a> concluded that pharmacologic inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27362227" 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="#62" class="mim-tip-reference" title="Zhao, Z. J., Zhao, R. <strong>Purification and cloning of PZR, a binding protein and putative physiological substrate of tyrosine phosphatase SHP-2.</strong> J. Biol. Chem. 273: 29367-29372, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792637</a>] [<a href="https://doi.org/10.1074/jbc.273.45.29367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792637">Zhao and Zhao (1998)</a> presented evidence indicating that MPZL1 (<a href="/entry/604376">604376</a>) and PTPNS1 (<a href="/entry/602461">602461</a>) are substrates for PTPN11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792637" 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 wildtype and Shp2 -/- mouse embryonic fibroblasts, <a href="#59" class="mim-tip-reference" title="Zannettino, A. C. W., Roubelakis, M., Welldon, K. J., Jackson, D. E., Simmons, P. J., Bendall, L. J., Henniker, A., Harrison, K. L., Niutta, S., Bradstock, K. F., Watt, S. M. <strong>Novel mesenchymal and haematopoietic cell isoforms of the SHP-2 docking receptor, PZR: identification, molecular cloning and effects on cell migration.</strong> Biochem. J. 370: 537-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12410637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12410637</a>] [<a href="https://doi.org/10.1042/BJ20020935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12410637">Zannettino et al. (2003)</a> found that full-length human PZR (MPZL1), which contains 2 intracellular Shp2-binding immunoreceptor tyrosine-based inhibitory motifs (ITIMs), promoted Shp2-dependent migration over a fibronectin (FN1; <a href="/entry/135600">135600</a>) substrate. PZR isoforms lacking the intracellular ITIMs did not promote Shp2-dependent cell migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12410637" 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>Helicobacter pylori CagA protein is injected from the attached H. pylori into host cells in the stomach and undergoes tyrosine phosphorylation. <a href="#20" class="mim-tip-reference" title="Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T, Asaka, M., Hatakeyama, M. <strong>SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.</strong> Science 295: 683-686, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743164</a>] [<a href="https://doi.org/10.1126/science.1067147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743164">Higashi et al. (2002)</a> demonstrated that wildtype but not phosphorylation-resistant CagA induces a growth factor-like response in gastric epithelial cells by forming a physical complex with SHP2 in a phosphorylation-dependent manner and stimulating the phosphatase activity. Disruption of the CagA-SHP2 complex abolishes the CagA-dependent cellular response. Conversely, the CagA effect on cells was reproduced by constitutively active SHP2. Thus, <a href="#20" class="mim-tip-reference" title="Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T, Asaka, M., Hatakeyama, M. <strong>SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.</strong> Science 295: 683-686, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743164</a>] [<a href="https://doi.org/10.1126/science.1067147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743164">Higashi et al. (2002)</a> concluded that upon translocation, CagA perturbs cellular functions by deregulating SHP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743164" 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="#30" class="mim-tip-reference" title="Kwon, J., Qu, C.-K., Maeng, J.-S., Falahati, R., Lee, C., Williams, M. S. <strong>Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.</strong> EMBO J. 24: 2331-2341, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15933714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15933714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15933714[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15933714">Kwon et al. (2005)</a> showed that activation of T-cell antigen receptor (see <a href="/entry/186880">186880</a>) in human Jurkat T cells and in mouse T-cell blasts induced transient inactivation of SHP2 by the oxidation of the SHP2 active site cysteine. SHP2 was recruited to the LAT (<a href="/entry/602354">602354</a>)-GADS (GRAP2; <a href="/entry/604518">604518</a>)-SLP76 (LCP2; <a href="/entry/601603">601603</a>) complex and regulated the phosphorylation of VAV1 (<a href="/entry/164875">164875</a>) and ADAP (FYB; <a href="/entry/602731">602731</a>). The association of ADAP with the SLP76 complex was regulated by SHP2 in a redox-dependent manner. <a href="#30" class="mim-tip-reference" title="Kwon, J., Qu, C.-K., Maeng, J.-S., Falahati, R., Lee, C., Williams, M. S. <strong>Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.</strong> EMBO J. 24: 2331-2341, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15933714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15933714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15933714[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15933714">Kwon et al. (2005)</a> concluded that TCR-mediated ROS generation leads to SHP2 oxidation, which promotes T-cell adhesion through effects on SLP76-dependent signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15933714" 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="#26" class="mim-tip-reference" title="Kikkawa, N., Hanazawa, T., Fujimura, L., Nohata, N., Suzuki, H., Chazono, H., Sakurai, D., Horiguchi, S., Okamoto, Y., Seki, N. <strong>miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC).</strong> Brit. J. Cancer 103: 877-884, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20700123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20700123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20700123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.bjc.6605811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20700123">Kikkawa et al. (2010)</a> identified a putative microRNA-489 (MIR489; <a href="/entry/614523">614523</a>) target site in the 3-prime UTR of PTPN11, which encodes a protein tyrosine phosphatase that can activate RAS (HRAS; <a href="/entry/190020">190020</a>)-MAP kinase (see <a href="/entry/176948">176948</a>) signaling in response to growth factors and cytokines. Overexpression of MIR489 in a human squamous cell carcinoma cell line reduced PTPN11 mRNA and protein expression and inhibited expression of a reporter gene containing a partial PTPN11 3-prime UTR. PTPN11 mRNA expression was significantly higher in hypopharyngeal squamous cell carcinomas compared with adjacent normal tissue from 16 patients. In contrast, MIR489 was downregulated in hypopharyngeal squamous cell carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20700123" 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 RNA pull-down assays and mass spectrometric analysis, <a href="#63" class="mim-tip-reference" title="Zheng, J., Huang, X., Tan, W., Yu, D., Du, Z., Chang, J., Wei, L., Han, Y., Wang, C., Che, X., Zhou, Y., Miao, X., and 12 others. <strong>Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.</strong> Nature Genet. 48: 747-757, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27213290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27213290</a>] [<a href="https://doi.org/10.1038/ng.3568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27213290">Zheng et al. (2016)</a> found that the long intergenic noncoding RNA LINC00673 (<a href="/entry/617079">617079</a>) interacted with PTPN11, which promotes cell growth and proliferation by activating SRC (<a href="/entry/190090">190090</a>)-ERK (see <a href="/entry/176948">176948</a>) signaling and inhibiting STAT1 (<a href="/entry/600555">600555</a>) signaling. RNA immunoprecipitation assays confirmed interaction of PTPN11 with LINC00673, which promoted ubiquitination and degradation of PTPN11. LINC00673 interacted with the E3 ubiquitin ligase PRPF19 (<a href="/entry/608330">608330</a>) and appeared to mediate and strengthen the interaction between PTPN11 and PRPF19, enhancing PRPF19-mediated ubiquitination and degradation of PTPN11. <a href="#63" class="mim-tip-reference" title="Zheng, J., Huang, X., Tan, W., Yu, D., Du, Z., Chang, J., Wei, L., Han, Y., Wang, C., Che, X., Zhou, Y., Miao, X., and 12 others. <strong>Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.</strong> Nature Genet. 48: 747-757, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27213290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27213290</a>] [<a href="https://doi.org/10.1038/ng.3568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27213290">Zheng et al. (2016)</a> concluded that LINC00673 plays a role in maintenance of cellular homeostasis by regulating PTPN11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27213290" 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="#15" class="mim-tip-reference" title="Dong, L., Yu, W.-M., Zheng, H., Loh, M. L., Bunting, S. T., Pauly, M., Huang, G., Zhou, M., Broxmeyer, H. E., Scadden, D. T., Qu, C.-K. <strong>Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment.</strong> Nature 539: 304-308, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27783593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27783593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27783593[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/nature20131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27783593">Dong et al. (2016)</a> reported that Ptpn11 activating mutations in the mouse bone marrow microenvironment promoted the development and progression of myeloproliferative neoplasm (MPN) through profound detrimental effects on hematopoietic stem cells. Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, caused excessive production of the CC chemokine CCL3 (<a href="/entry/182283">182283</a>), which recruited monocytes to the area in which hematopoietic stem cells also resided. Consequently, hematopoietic stem cells were hyperactivated by interleukin-1-beta (IL1B; <a href="/entry/147720">147720</a>) and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reversed MPN development induced by the Ptpn11-mutated bone marrow microenvironment. <a href="#15" class="mim-tip-reference" title="Dong, L., Yu, W.-M., Zheng, H., Loh, M. L., Bunting, S. T., Pauly, M., Huang, G., Zhou, M., Broxmeyer, H. E., Scadden, D. T., Qu, C.-K. <strong>Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment.</strong> Nature 539: 304-308, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27783593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27783593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27783593[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/nature20131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27783593">Dong et al. (2016)</a> concluded that their study revealed the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukemogenesis and identified CCL3 as a potential therapeutic target for controlling leukemic progression in Noonan syndrome (<a href="/entry/163950">163950</a>) and for improving stem cell transplantation therapy in Noonan syndrome-associated leukemias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27783593" 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>Noonan Syndrome 1</em></strong></p><p>
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In more than 50% of patients with Noonan syndrome (see NS1, <a href="/entry/163950">163950</a>), <a href="#51" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. <strong>Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.</strong> Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704759</a>] [<a href="https://doi.org/10.1038/ng772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704759">Tartaglia et al. (2001)</a> identified mutations in the PTPN11 gene (see, e.g., <a href="#0001">176876.0001</a>-<a href="#0003">176876.0003</a>). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP-2 activity underlie the pathogenesis of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704759" 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="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a> identified a PTPN11 mutation (<a href="#0004">176876.0004</a>) in a family inheriting Noonan syndrome with multiple giant cell lesions in bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11992261" 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 direct DNA sequencing, <a href="#32" class="mim-tip-reference" title="Maheshwari, M., Belmont, J., Fernbach, S., Ho, T., Molinari, L., Yakub, I., Yu, F., Combes, A., Towbin, J., Craigen, W. J., Gibbs, R. <strong>PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.</strong> Hum. Mutat. 20: 298-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325025</a>] [<a href="https://doi.org/10.1002/humu.10129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325025">Maheshwari et al. (2002)</a> surveyed 16 subjects with the clinical diagnosis of Noonan syndrome from 12 families and their relevant family members for mutations in the PTPN11/SHP2 gene, and found 3 different mutations among 5 families. Two unrelated subjects shared a de novo ser502-to-thr (S502T; <a href="#0007">176876.0007</a>) substitution in exon 13; 2 additional unrelated families had a tyr63-to-cys (Y63C; <a href="#0008">176876.0008</a>) mutation in exon 3; and 1 subject had a tyr62-to-asp (Y62D; <a href="#0009">176876.0009</a>) substitution, also in exon 3. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N-terminal SH2 domain and the phosphatase catalytic domain. Six of 8 subjects with mutations had pulmonary valve stenosis, while no mutations were identified in 4 subjects with hypertrophic cardiomyopathy. An additional 4 subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11 were identified. These results confirmed that mutations in PTPN11 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 gives rise to Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325025" 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="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> analyzed the PTPN11 gene in 21 Japanese patients with Noonan syndrome. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed 6 different heterozygous missense mutations in 7 cases. The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161469" 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="#33" class="mim-tip-reference" title="Musante, L., Kehl, H. G., Majewski, F., Meinecke, P., Schweiger, S., Gillessen-Kaesbach, G., Wieczorek, D., Hinkel, G. K., Tinschert, S., Hoeltzenbein, M., Ropers, H.-H., Kalscheuer, V. M. <strong>Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.</strong> Europ. J. Hum. Genet. 11: 201-206, 2003. Note: Erratum: Europ. J. Hum. Genet. 11: 551 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634870</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634870">Musante et al. (2003)</a> screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients. They identified 15 mutations, all of which were missense mutations; 11 of them were located in exon 3, which encodes the N-SH2 domain. No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of the patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the group of 64 patients without PTPN11 mutations suggested further genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12634870" 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="#48" class="mim-tip-reference" title="Tartaglia, M., Cordeddu, V., Chang, H., Shaw, A., Kalidas, K., Crosby, A., Patton, M. A., Sorcini, M., van der Burgt, I., Jeffery, S., Gelb, B. D. <strong>Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome.</strong> Am. J. Hum. Genet. 75: 492-497, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15248152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15248152</a>] [<a href="https://doi.org/10.1086/423493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15248152">Tartaglia et al. (2004)</a> investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in Noonan syndrome. By analyzing intronic positions that flank the exonic PTPN11 lesions in 49 sporadic Noonan syndrome cases, they traced the parental origin of mutations in 14 families. All mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. They also found advanced paternal age among cohorts of sporadic Noonan syndrome cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic Noonan syndrome caused by PTPN11 mutations, as well as in families inheriting the disorder. They favored sex-specific developmental effects as the explanation for the sex-ratio distortion in PTPN11-associated Noonan syndrome, because fetal lethality has been documented in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15248152" 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="#57" class="mim-tip-reference" title="Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. <strong>Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 89: 3359-3364, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240615</a>] [<a href="https://doi.org/10.1210/jc.2003-032091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240615">Yoshida et al. (2004)</a> reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (<a href="#0024">176876.0024</a>) and 10 recurrent missense mutations in 18 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M. <strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong> Am. J. Med. Genet. 143A: 1249-1252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17497712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17497712</a>] [<a href="https://doi.org/10.1002/ajmg.a.31738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17497712">Becker et al. (2007)</a> reported what they stated was the first known case of compound heterozygosity for NS-causing mutations in the PTPN11 gene (see <a href="#0004">176876.0004</a> and <a href="#0008">176876.0008</a>), resulting in early fetal death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497712" 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="#45" class="mim-tip-reference" title="Shchelochkov, O. A., Patel, A., Weissenberger, G. M., Chinault, A. C., Wiszniewska, J., Fernandes, P. H., Eng, C., Kukolich, M. K., Sutton, V. R. <strong>Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome.</strong> Am. J. Med. Genet. 146A: 1042-1048, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348260</a>] [<a href="https://doi.org/10.1002/ajmg.a.32215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348260">Shchelochkov et al. (2008)</a> and <a href="#18" class="mim-tip-reference" title="Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M. <strong>Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.</strong> Am. J. Med. Genet. 149A: 2122-2128, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19760651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19760651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19760651[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.32992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19760651">Graham et al. (2009)</a> reported 2 unrelated patients with a Noonan syndrome phenotype associated with respective 10-Mb and 8.98-Mb duplications on chromosome 12q24.13, encompassing the PTPN11 gene. <a href="#18" class="mim-tip-reference" title="Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M. <strong>Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.</strong> Am. J. Med. Genet. 149A: 2122-2128, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19760651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19760651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19760651[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.32992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19760651">Graham et al. (2009)</a> did not identify additional duplications in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. <a href="#18" class="mim-tip-reference" title="Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M. <strong>Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.</strong> Am. J. Med. Genet. 149A: 2122-2128, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19760651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19760651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19760651[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.32992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19760651">Graham et al. (2009)</a> concluded that duplication of PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18348260+19760651" 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>Patients affected with cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) present with symptoms that some considered to represent a more severe expression of Noonan syndrome, namely, congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. Because mutations in PTPN11 are responsible for Noonan syndrome, <a href="#22" class="mim-tip-reference" title="Ion, A., Tartaglia, M., Song, X., Kalidas, K., van der Burgt, I., Shaw, A. C., Ming, J. E., Zampino, G., Zackai, E. H., Dean, J. C. S., Somer, M., Parenti, G., Crosby, A. H., Patton, M. A., Gelb, B. D., Jeffery, S. <strong>Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.</strong> Hum. Genet. 111: 421-427, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384786</a>] [<a href="https://doi.org/10.1007/s00439-002-0803-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384786">Ion et al. (2002)</a> investigated the possibility that this gene may be involved in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC 'based on OMIM diagnostic criteria' was examined for mutations in the PTPN11 coding sequence by means of denaturing high-performance liquid chromatography (DHPLC). No abnormalities in the coding region of the gene were found in any patient, nor any evidence of major deletions within the gene. <a href="#33" class="mim-tip-reference" title="Musante, L., Kehl, H. G., Majewski, F., Meinecke, P., Schweiger, S., Gillessen-Kaesbach, G., Wieczorek, D., Hinkel, G. K., Tinschert, S., Hoeltzenbein, M., Ropers, H.-H., Kalscheuer, V. M. <strong>Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.</strong> Europ. J. Hum. Genet. 11: 201-206, 2003. Note: Erratum: Europ. J. Hum. Genet. 11: 551 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634870</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634870">Musante et al. (2003)</a> screened for mutations in the PTPN11 gene in 5 sporadic patients with CFC syndrome and found none. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12634870+12384786" 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 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, <a href="#43" class="mim-tip-reference" title="Schollen, E., Matthijs, G., Gewillig, M., Fryns, J.-P., Legius, E. <strong>PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.</strong> Europ. J. Hum. Genet. 11: 85-88, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529711</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529711">Schollen et al. (2003)</a> identified a missense mutation in the PTPN11 gene (<a href="#0018">176876.0018</a>). The mutation was not found in 7 unaffected relatives or 3 spouses. The authors noted that in D. melanogaster and C. elegans, the Ptpn11 gene has been implicated in oogenesis. In this family, there were 3 sets of dizygotic twins among the offspring of 2 affected females, suggesting that PTPN11 might also be involved in oogenesis and twinning in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529711" 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="Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E. <strong>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.</strong> Am. J. Med. Genet. 130A: 378-383, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15384080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15384080</a>] [<a href="https://doi.org/10.1002/ajmg.a.30270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15384080">Bertola et al. (2004)</a> described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement, developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (<a href="#0019">176876.0019</a>); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15384080" 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>LEOPARD Syndrome 1</em></strong></p><p>
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LEOPARD syndrome (LPRD1; <a href="/entry/151100">151100</a>) is an autosomal dominant disorder characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects, sharing several clinical features with Noonan syndrome. <a href="#14" class="mim-tip-reference" title="Digilio, M. C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B. <strong>Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.</strong> Am. J. Hum. Genet. 71: 389-394, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12058348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12058348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12058348[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/10.1086/341528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12058348">Digilio et al. (2002)</a> screened 9 patients with LEOPARD syndrome (including a mother-daughter pair), and 2 children with Noonan syndrome who had multiple cafe-au-lait spots, for mutations in the PTPN11 gene. In 10 of the 11 patients, they found 1 of 2 novel missense mutations: Y27C (<a href="#0005">176876.0005</a>) in exon 7 or T468M (<a href="#0006">176876.0006</a>) in exon 12. Both mutations affected the PTPN11 phosphotyrosine phosphatase domain, which is involved in less than 30% of the Noonan syndrome PTPN11 mutations. This study demonstrated that LEOPARD syndrome and Noonan syndrome are allelic disorders. The detected mutations suggested that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the LEOPARD syndrome subtype of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12058348" 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="#28" class="mim-tip-reference" title="Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. <strong>PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.</strong> J. Biol. Chem. 281: 6785-6792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377799</a>] [<a href="https://doi.org/10.1074/jbc.M513068200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377799">Kontaridis et al. (2006)</a> examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see <a href="/entry/176948">176948</a>)-mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. <a href="#28" class="mim-tip-reference" title="Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. <strong>PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.</strong> J. Biol. Chem. 281: 6785-6792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377799</a>] [<a href="https://doi.org/10.1074/jbc.M513068200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377799">Kontaridis et al. (2006)</a> concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16377799" 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 4 of 6 Japanese patients with LEOPARD syndrome, <a href="#58" class="mim-tip-reference" title="Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T. <strong>Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (Letter)</strong> Am. J. Med. Genet. 130A: 432-434, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389709</a>] [<a href="https://doi.org/10.1002/ajmg.a.30281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389709">Yoshida et al. (2004)</a> identified 1 of 3 heterozygous missense mutations: tyr279 to cys (Y279C), ala461 to thr (A461T; <a href="#0020">176876.0020</a>), or gly464 to ala (G464A; <a href="#0021">176876.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15389709" 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 a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, <a href="#2" class="mim-tip-reference" title="Alfurayh, N., Alsaif, F., Alballa, N., Zeitouni, L., Ramzan, K., Imtiaz, F., Alakeel, A. <strong>LEOPARD syndrome with PTPN11 gene mutation in three family members presenting with different phenotypes.</strong> J. Pediat. Genet. 9: 246-251, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32765928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32765928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32765928[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/10.1055/s-0039-3400226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32765928">Alfurayh et al. (2020)</a> identified heterozygosity for the Y279C mutation (<a href="#0005">176876.0005</a>) in the PTPN11 gene. The mutation was identified by next-generation sequencing. The father had normal stature, hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, normal stature, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32765928" 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>Juvenile Myelomonocytic Leukemia</em></strong></p><p>
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Juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), a disorder with excessive proliferation of myelomonocytic cells, constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. JMML is observed occasionally in patients with Noonan syndrome, leading <a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> to consider whether defects in PTPN11 are present in myeloid disorders. In 5 unrelated children with Noonan syndrome and JMML, they found heterozygosity with respect to a mutation in exon 3 of PTPN11. Four of the children shared the same mutation (218C-T; <a href="#0011">176876.0011</a>). In 2 unrelated individuals with growth retardation, pulmonic stenosis, and JMML, they found missense defects in PTPN11: the 218C-T transition, and a defect in exon 13 affecting the protein tyrosine phosphatase domain. Analysis of germline and parental DNAs for these 6 cases indicated that the mutations were de novo germline events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> also identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML but without Noonan syndrome, with 9 different molecular defects in exon 3 and 1 in exon 13. Nonhematologic DNAs were available for 9 individuals with a mutation in PTPN11 in their leukemic cells, and none harbored the defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> identified no mutation in PTPN11 among 8 individuals with JMML and neurofibromatosis type I (<a href="/entry/162200">162200</a>). Molecular screening for mutations in exons 1 and 2 of NRAS (<a href="/entry/164790">164790</a>) and KRAS2 (<a href="/entry/190070">190070</a>) identified defects in 5 and 7 individuals with isolated cases of JMML, respectively, none of whom harbored a mutation in PTPN11. This indicated that defects in RAS, neurofibromin, and SHP2, all involved in regulation of the MAPK cascade, are mutually exclusive in JMML. Comparison of phenotypes and karyotypes did not identify differences between individuals with JMML who did or did not have mutations in PTPN11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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>Other Malignancies</em></strong></p><p>
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<a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> investigated the prevalence of somatic mutations in PTPN11 among 50 children with myelodysplastic syndrome. They identified no mutation among 23 children with refractory anemia, but observed missense mutations in exon 3 in 5 of 27 children with an excess of blasts. Three of these mutations were also associated with JMML in other patients. Among 24 children with de novo AML (<a href="/entry/601626">601626</a>), they identified a novel trinucleotide substitution in an infant with acute monoblastic leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., Maris, J. M., Richardson, A., Bardelli, A., Sugarbaker, D. J., Richards, W. G., Du, J., and 9 others. <strong>Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia.</strong> Cancer Res. 64: 8816-8820, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15604238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15604238</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-04-1923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15604238">Bentires-Alj et al. (2004)</a> demonstrated that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma (<a href="/entry/256700">256700</a>) and AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15604238" 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>Metachondromatosis</em></strong></p><p>
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Using whole-genome sequencing in 1 affected individual from a 5-generation family with metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#46" class="mim-tip-reference" title="Sobreira, N. L. M., Cirulli, E. T., Avramopoulos, D., Wohler, E., Oswald, G. L., Stevens, E. L., Ge, D., Shianna, K. V., Smith, J. P., Maia, J. M., Gumbs, C. E., Pevsner, J., Thomas, G., Valle, D., Hoover-Fong, J. E., Goldstein, D. B. <strong>Whole-genome sequencing of a single proband together with linkage analysis identifies a mendelian disease gene.</strong> PLoS Genet. 6: e1000991, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20577567[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577567">Sobreira et al. (2010)</a> identified a heterozygous 11-bp deletion in the PTPN11 gene (<a href="#0025">176876.0025</a>) that segregated with the disease. Sequencing of PTPN11 in another family with metachondromatosis revealed a heterozygous nonsense mutation (<a href="#0026">176876.0026</a>) in affected individuals. Neither mutation was detected in 469 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> used a targeted array to capture exons and promoter sequences from an 8.6-Mb linked interval in 16 participants from 11 metachondromatosis families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. By this method, they identified heterozygous putative loss-of-function mutations in the PTPN11 gene in 4 of the 11 families (<a href="#0028">176876.0028</a>-<a href="#0031">176876.0031</a>). Sanger sequence analysis of PTPN11 coding regions in the 7 remaining families and in 6 additional metachondromatosis families identified novel heterozygous mutations in 4 families (<a href="#0032">176876.0032</a>-<a href="#0035">176876.0035</a>). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an METCDS patient with a 15-kb deletion spanning exon 7 of PTPN11 (<a href="#0036">176876.0036</a>). In total, of 17 METCDS families, <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified mutations in 11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each family had a different mutation, and the mutations were scattered across the gene. Microdissected METCDS lesions from 2 patients with PTPN11 mutations demonstrated loss of heterozygosity for the wildtype allele. <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> suggested that metachondromatosis may be genetically heterogeneous because 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" 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="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a> reported the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. They found mutations in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense and several were recurrent. Pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them: 70.6% vs 46.2% (P less than 0.01); hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations: 5.9% vs 26.2%; (P less than 0.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the 2 groups. A PTPN11 mutation was identified in a family inheriting Noonan syndrome with multiple giant cell lesions in bone, extending the phenotypic range of disease associated with this gene (see <a href="#0004">176876.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11992261" 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="#40" class="mim-tip-reference" title="Sarkozy, A., Conti, E., Seripa, D., Digilio, M. C., Grifone, N., Tandoi, C., Fazio, V. M., Di Ciommo, V., Marino, B., Pizzuti, A., Dallapiccola, B. <strong>Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndrome. (Letter)</strong> J. Med. Genet. 40: 704-708, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960218</a>] [<a href="https://doi.org/10.1136/jmg.40.9.704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960218">Sarkozy et al. (2003)</a> analyzed the PTPN11 gene in 71 Italian patients with Noonan syndrome and 13 with multiple lentigines/LEOPARD syndrome (ML/LS) and identified 14 different missense mutations in 34 patients, 23 with Noonan syndrome and 11 with ML/LS. The distribution of congenital heart defects was markedly different between the 2 groups. Pulmonary valve stenosis, the most common congenital heart defect in Noonan syndrome, was related to an exon 8 mutation hotspot at residue asn308 (see, e.g., <a href="#0003">176876.0003</a> and <a href="#0004">176876.0004</a>), whereas hypertrophic cardiomyopathy, predominant in patients with ML/LS, was associated with mutations in exon 7 (see, e.g., Y279C, <a href="#0005">176876.0005</a>) and exon 12 (see, e.g., T468M, <a href="#0006">176876.0006</a>). Atrial septal defects were related to exon 3 mutations (see, e.g., Y62D, <a href="#0009">176876.0009</a>), whereas atrioventricular canal defects and mitral valve anomalies were found in association with different exon mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960218" 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="#35" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Ohashi, H., Kurosawa, K., Kondoh, T., Ishikiriyama, S., Kawame, H., Kamasaki, H., Yamanaka, T., Takada, F., Nishio, K., Sakurai, M., Tamai, H., Nagashima, T., Suzuki, Y., Kure, S., Fujii, K., Imaizumi, M., Matsubara, Y. <strong>Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.</strong> J. Hum. Genet. 50: 192-202, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15834506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15834506</a>] [<a href="https://doi.org/10.1007/s10038-005-0239-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15834506">Niihori et al. (2005)</a> identified PTPN11 mutations in 16 of 41 patients with Noonan syndrome and 3 of 29 patients with childhood leukemia. Immune complex tyrosine phosphatase assays showed that all the mutations resulted in increased phosphatase activity compared to wildtype. Several mutations in the N-SH2 domain, including T73I (<a href="#0011">176876.0011</a>), showed a 6- to 12-fold increase in activity. Other N-SH2 mutations (Y63C; <a href="#0008">176876.0008</a> and Q79R; <a href="#0018">176876.0018</a>) and PTP-domain mutations (N308D; <a href="#0003">176876.0003</a> and S502T; <a href="#0007">176876.0007</a>) showed a 2- to 4-fold increase in activity. These results and a review of previously reported cases indicated that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis. Two mutations associated with Noonan syndrome failed to promote the RAS/MAPK downstream signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15834506" 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="#50" class="mim-tip-reference" title="Tartaglia, M., Martinelli, S., Stella, L., Bocchinfuso, G., Flex, E., Cordeddu, V., Zampino, G., van der Burgt, I., Palleschi, A., Petrucci, T. C., Sorcini, M., Schoch, C., Foa, R., Emanuel, P. D., Gelb, B. D. <strong>Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.</strong> Am. J. Hum. Genet. 78: 279-290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16358218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16358218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16358218[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/10.1086/499925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16358218">Tartaglia et al. (2006)</a> proposed a model that splits Noonan syndrome- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, they investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP2 proteins recurring in Noonan syndrome, LEOPARD syndrome, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that Noonan syndrome-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. Furthermore, they showed that the recurrent LEOPARD syndrome-causing Y279C (<a href="#0005">176876.0005</a>) and T468M (<a href="#0006">176876.0006</a>) amino acid substitutions engender loss of SHP2 catalytic activity, identifying a previously unrecognized behavior of this class of missense PTPN11 mutations. By molecular modeling and biochemical studies, <a href="#28" class="mim-tip-reference" title="Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. <strong>PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.</strong> J. Biol. Chem. 281: 6785-6792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377799</a>] [<a href="https://doi.org/10.1074/jbc.M513068200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377799">Kontaridis et al. (2006)</a> showed that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. They concluded that pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16358218+16377799" 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="#57" class="mim-tip-reference" title="Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. <strong>Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 89: 3359-3364, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240615</a>] [<a href="https://doi.org/10.1210/jc.2003-032091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240615">Yoshida et al. (2004)</a> reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. They identified 11 mutations in 18 patients. Clinical assessment showed that the growth pattern was similar in mutation-positive and mutation-negative patients. Pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients, as was atrial septal defect, whereas hypertrophic cardiomyopathy was present in 5 mutation-negative patients only. Hematologic abnormalities such as bleeding diathesis and juvenile myelomonocytic leukemia were exclusively present in mutation-positive patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240615" 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="#31" class="mim-tip-reference" title="Limongelli, G., Sarkozy, A., Pacileo, G., Calabro, P., Digilio, M. C., Maddaloni, V., Gagliardi, G., Di Salvo, G., Iacomino, M., Marino, B., Dallapiccola, B., Calabro, R. <strong>Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome.</strong> Am. J. Med. Genet. 146A: 620-628, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18241070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18241070</a>] [<a href="https://doi.org/10.1002/ajmg.a.32206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18241070">Limongelli et al. (2008)</a> studied 24 LEOPARD syndrome patients, 16 with mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene (<a href="/entry/164760">164760</a>), and 6 in whom no mutation had been found. Patients without PTPN11 mutations showed a significantly higher frequency of family history of sudden death, increased left atrial dimensions, and cardiac arrhythmias, and seemed to be at higher risk for adverse cardiac events. Three patients with mutations in exon 13 of the PTPN11 gene had a severe form of biventricular obstructive LVH with early onset of heart failure symptoms, consistent with previous observations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18241070" 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>Atrioventricular and semilunar valve abnormalities are common birth defects. During studies of genetic interaction between Egr2 and Ptpn11, encoding the protein-tyrosine phosphatase Shp2, <a href="#10" class="mim-tip-reference" title="Chen, B., Bronson, R. T., Klaman, L. D., Hampton, T. G., Wang, J., Green, P. J., Magnuson, T., Douglas, P. S., Morgan, J. P., Neel, B. G. <strong>Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis.</strong> Nature Genet. 24: 296-299, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700187</a>] [<a href="https://doi.org/10.1038/73528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700187">Chen et al. (2000)</a> found that Egfr (<a href="/entry/131550">131550</a>) is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele 'waved-2' exhibited semilunar valve enlargement resulting from overabundant mesenchymal cells. Egfr -/- mice (on CD1 background) had similar defects. The penetrance and severity of the defects in the homozygous 'waved-2' mice were enhanced by heterozygosity for targeted mutation of exon 2 of Ptpn11. Compound mutant mice also showed premature lethality. Electrocardiography, echocardiography, and hemodynamic analyses showed that affected mice developed aortic stenosis and regurgitation. The results identified Egfr and Shp2 as components of a growth-factor signaling pathway required specifically for semilunar valvulogenesis, supported the hypothesis that Shp2 is required for Egfr signaling in vivo, and provided an animal model for aortic valve disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700187" 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>Shp2 can potentiate signaling for the MAP kinase pathway (see <a href="/entry/602425">602425</a>) and is required during early mouse development for gastrulation. Chimeric analysis can identify, by study of phenotypically normal embryos, tissues that tolerate mutant cells, and therefore do not require the mutated gene, or lack mutant cells and presumably require the mutated gene during the developmental history. <a href="#41" class="mim-tip-reference" title="Saxton, T. M., Ciruna, B. G., Holmyard, D., Kulkarni, S., Harpal, K., Rossant, J., Pawson, T. <strong>The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development.</strong> Nature Genet. 24: 420-423, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742110</a>] [<a href="https://doi.org/10.1038/74279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742110">Saxton et al. (2000)</a> therefore generated chimeric mouse embryos to explore the cellular requirements for Shp2. This analysis revealed an obligatory role for Shp2 during outgrowth of the limb. Shp2 is specifically required in mesenchyme cells of the progress zone, directly beneath the distal ectoderm of the limb bud. Comparison of Ptpn11 mutant and Fgfr1 (<a href="/entry/136350">136350</a>) mutant chimeric limbs indicated that in both cases mutant cells failed to contribute to the progress zone of phenotypically normal chimeras, leading to the hypothesis that a signal transduction pathway, initiated by Fgfr1 and acting through Shp2, is essential within progress zone cells. Rather than integrating proliferative signals, Shp2 probably exerts its effects on limb development by influencing cell shape, movement, or adhesion. Furthermore, the branchial arches, which also use Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates phosphotyrosine-signaling events during the complex ectodermal-mesenchymal interactions that regulate mammalian budding morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742110" 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="#42" class="mim-tip-reference" title="Saxton, T. M., Henkemeyer, M., Gasca, S., Shen, R., Rossi, D. J., Shalaby, F., Feng, G.-S., Pawson, T. <strong>Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2.</strong> EMBO J. 16: 2352-2364, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171349</a>] [<a href="https://doi.org/10.1093/emboj/16.9.2352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171349">Saxton et al. (1997)</a> generated mice deficient in Shp2 by targeted disruption. Homozygous Shp2 -/- mice die at midgestation with multiple defects in mesodermal patterning, while heterozygous mutants appear normal. <a href="#39" class="mim-tip-reference" title="Qu, C.-K., Yu, W.-M., Azzarelli, B., Cooper, S., Broxmeyer, H. E., Feng, G.-S. <strong>Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells.</strong> Molec. Cell. Biol. 18: 6075-6082, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9742124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9742124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9742124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.18.10.6075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9742124">Qu et al. (1998)</a> aggregated homozygous mutant embryonic stem (ES) cells and wildtype embryos to create Shp2 -/- wildtype chimeric animals. They reported an essential role of Shp2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp2 -/- progenitors for erythroid or myeloid cells were detected in the fetal liver or bone marrow of chimeric animals by using the in vitro colony forming unit (CFU) assay. Furthermore, hematopoiesis was defective in Shp2 -/- yolk sacs. In addition, the Shp2 mutant caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathologic changes in the lungs, intestines, and skin. <a href="#39" class="mim-tip-reference" title="Qu, C.-K., Yu, W.-M., Azzarelli, B., Cooper, S., Broxmeyer, H. E., Feng, G.-S. <strong>Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells.</strong> Molec. Cell. Biol. 18: 6075-6082, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9742124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9742124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9742124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.18.10.6075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9742124">Qu et al. (1998)</a> concluded that Shp2 is involved in the differentiation of multiple tissue-specific cells and in body organization. They suggested that the requirement for Shp2 appears to be more stringent in hematopoiesis than in other systems. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9742124+9171349" 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 mouse and zebrafish models, <a href="#37" class="mim-tip-reference" title="Paardekooper Overman, J., Yi, J.-S., Bonetti, M., Soulsby, M., Preisinger, C., Stokes, M. P., Hui, L., Silva, J. C., Overvoorde, J., Giansanti, P., Heck, A. J. R., Kontaridis, M. I., den Hertog, J., Bennett, A. M. <strong>PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice.</strong> Molec. Cell. Biol. 34: 2874-2889, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24865967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24865967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24865967[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00135-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24865967">Paardekooper Overman et al. (2014)</a> found that both Shp2 activating mutations associated with Noonan syndrome and Shp2 inactivating mutations associated with LEOPARD syndrome caused tyrosine hyperphosphorylation of Pzr. Immunoprecipitation analysis indicated that the mutations, which result in an open Shp2 conformation, increased association of the tyrosine kinase Src (<a href="/entry/190090">190090</a>) with Shp2 and Pzr, suggesting a pathway for Pzr hyperphosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24865967" 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="#60" class="mim-tip-reference" title="Zhang, E. E., Chapeau, E., Hagihara, K., Feng, G.-S. <strong>Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism.</strong> Proc. Nat. Acad. Sci. 101: 16064-16069, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520383[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405041101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520383">Zhang et al. (2004)</a> selectively deleted Shp2 in postmitotic forebrain neurons of mice and observed the development of early-onset obesity with increased serum levels of leptin (<a href="/entry/164160">164160</a>), insulin (<a href="/entry/176730">176730</a>), glucose, and triglycerides, although the mutant mice were not hyperphagic. In wildtype mice, the authors found that Shp2 downregulation of Jak2 (<a href="/entry/147796">147796</a>)/Stat3 (<a href="/entry/102582">102582</a>) activation by leptin in the hypothalamus was offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see <a href="/entry/601795">601795</a>) pathway; thus, Shp2 deletion in the brain results in induction rather than suppression of leptin resistance. <a href="#60" class="mim-tip-reference" title="Zhang, E. E., Chapeau, E., Hagihara, K., Feng, G.-S. <strong>Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism.</strong> Proc. Nat. Acad. Sci. 101: 16064-16069, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520383[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405041101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520383">Zhang et al. (2004)</a> suggested that a primary function of SHP2 in the postmitotic forebrain is to control energy balance and metabolism, and that SHP2 is a critical signaling component of the leptin receptor (<a href="/entry/601007">601007</a>) in the hypothalamus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520383" 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 a constitutively active mouse Shp2 mutant, <a href="#19" class="mim-tip-reference" title="He, Z., Zhang, S. S., Meng, Q., Li, S., Zhu, H. H., Raquil, M.-A., Alderson, N., Zhang, H., Wu, J., Rui, L., Cai, D., Feng, G.-S. <strong>Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals.</strong> Molec. Cell. Biol. 32: 1867-1878, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22431513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22431513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22431513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.06712-11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22431513">He et al. (2012)</a> found that Shp2 integrated leptin and estrogen signaling in transgenic female mice. Transgenic females, but not males, were resistant to high-fat diet-induced obesity and liver steatosis via enhanced leptin and insulin sensitivity and downstream ERK activation. SHP2 and estrogen receptor-alpha (ESR1; <a href="/entry/133430">133430</a>) interacted directly in MCF-7 cells and female mouse tissues, and the interaction was enhanced by estrogen stimulation. Ovariectomy of transgenic mice reversed their resistance to high-fat diet-induced obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22431513" 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="#34" class="mim-tip-reference" title="Nakamura, T., Colbert, M., Krenz, M., Molkentin, J. D., Hahn, H. S., Dorn, G. W., II, Robbins, J. <strong>Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome.</strong> J. Clin. Invest. 117: 2123-2132, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17641779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17641779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17641779[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/10.1172/JCI30756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17641779">Nakamura et al. (2007)</a> generated Q79R (<a href="#0018">176876.0018</a>) transgenic mice in which the mutated protein was expressed in cardiomyocytes either during gestation or following birth. Q79R Shp2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, whereas in the postnatal cardiomyocyte, Q79R Shp2 expression was benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway (see <a href="/entry/176948">176948</a>), and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2. <a href="#34" class="mim-tip-reference" title="Nakamura, T., Colbert, M., Krenz, M., Molkentin, J. D., Hahn, H. S., Dorn, G. W., II, Robbins, J. <strong>Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome.</strong> J. Clin. Invest. 117: 2123-2132, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17641779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17641779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17641779[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/10.1172/JCI30756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17641779">Nakamura et al. (2007)</a> concluded that there are developmental stage-specific effects of Q79R cardiac expression in Noonan syndrome, and that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17641779" 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 cultured mouse embryonic cortical precursor cells, <a href="#17" class="mim-tip-reference" title="Gauthier, A. S., Furstoss, O., Araki, T., Chan, R., Neel, B. G., Kaplan, D. R., Miller, F. D. <strong>Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome.</strong> Neuron 54: 245-262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17442246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17442246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17442246[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.neuron.2007.03.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17442246">Gauthier et al. (2007)</a> found that Shp2 enhanced neurogenesis and inhibited cytokine-mediated astrocytosis. Inhibition of Shp2 resulted in decreased neurogenesis, aberrant migration of neurons, and premature gliogenesis. Expression of a Noonan syndrome-associated Shp2 mutant with enhanced activity promoted neurogenesis and inhibited astrogenesis in vitro and in vivo. Further studies showed that Shp2 promotes neurogenesis via activation of the MEK-ERK pathway, and inhibits gliogenesis by suppressing the gp130 (IL6ST; <a href="/entry/600694">600694</a>)-JAK-STAT pathway. <a href="#17" class="mim-tip-reference" title="Gauthier, A. S., Furstoss, O., Araki, T., Chan, R., Neel, B. G., Kaplan, D. R., Miller, F. D. <strong>Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome.</strong> Neuron 54: 245-262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17442246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17442246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17442246[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.neuron.2007.03.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17442246">Gauthier et al. (2007)</a> suggesting that the cognitive impairment observed in some patients with Noonan syndrome may result from aberrant neuron cell-fate and a perturbation in the relative ratios of these brain cell types during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17442246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the developmental effects of the Y279C and T468M mutations in the PTPN11 gene, <a href="#36" class="mim-tip-reference" title="Oishi, K., Zhang, H., Gault, W. J., Wang, C. J., Tan, C. C., Kim, I.-K., Ying, H., Rahman, T., Pica, N., Tartaglia, M., Mlodzik, M., Gelb, B. D. <strong>Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development.</strong> Hum. Molec. Genet. 18: 193-201, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18849586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18849586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18849586[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18849586">Oishi et al. (2009)</a> generated the equivalent mutations in the orthologous Drosophila corkscrew (csw) gene. Ubiquitous expression of the mutant csw alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were gain-of-function phenotypes mediated by increased RAS/MAPK signaling and requiring the residual phosphatase activity of the mutant Y279C and T468M alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18849586" 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="#38" class="mim-tip-reference" title="Princen, F., Bard, E., Sheikh, F., Zhang, S. S., Wang, J., Zago, W. M., Wu, D., Trelles, R. D., Bailly-Maitre, B., Kahn, C. R., Chen, Y., Reed, J. C., Tong, G. G., Mercola, M., Chen, J., Feng, G.-S. <strong>Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death.</strong> Molec. Cell. Biol. 29: 378-388, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19001090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19001090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19001090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01661-08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19001090">Princen et al. (2009)</a> created mice with deletion of Shp2 directed to striated muscle. Homozygous mutant mice were born at the expected frequency, but developed severe dilated cardiomyopathy, resulting in heart failure and death within 2 weeks of birth. Development of cardiomyopathy was associated with insulin resistance, glucose intolerance, and impaired insulin-stimulated glucose uptake in striated muscle. No significant abnormalities were observed in other tissues and organs, including skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19001090" 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="#54" class="mim-tip-reference" title="Xu, D., Wang, S., Yu, W.-M., Chan, G., Araki, T., Bunting, K. D., Neel, B. G., Qu, C.-K. <strong>A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells.</strong> Blood 116: 3611-3621, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20651068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20651068</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20651068[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/10.1182/blood-2010-01-265652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20651068">Xu et al. (2010)</a> found that mice with a germline heterozygous D61G mutation (<a href="#0010">176876.0010</a>) developed a JMML-like myeloproliferative disorder with excessive myeloid expansion in the bone marrow and spleen. Homozygous mutant mice were embryonic lethal due to cardiac developmental defects. Heterozygous mutant mice had higher levels of short- and long-term hematopoietic stem cells in the bone marrow and spleen compared to wildtype mice. Stem cells from heterozygous mutant mice showed enhanced entry of quiescent stem cells (G0 phase) into the cell cycle, as well as decreased apoptosis, and showed a greater long-term repopulating ability in transplanted mice compared to wildtype cells. Primary and secondary recipient mice transplanted with D61G-mutant bone marrow cells or purified lineage-negative Sca1+/Kit+ (LSK) cells developed a myeloproliferative disorder, suggesting that the pathogenic effects of the Ptpn11 mutation are cell autonomous and occur at the level of the hematopoietic stem cell. D61G-mutant cells also showed an enhanced response to stimulation with IL3 (<a href="/entry/147740">147740</a>). Studies with heterozygous D61G/Gab2 (<a href="/entry/606203">606203</a>)-null mice and cells showed attenuation of the increased number of stem cells, indicating that Gab2 is an important mediator of the myeloproliferative disorder induced by the D61G mutation. Gab2 is a prominent PTPN11-interacting protein with a role in cell signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20651068" 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="#44" class="mim-tip-reference" title="Sharma, N., Kumar, V., Everingham, S., Mali, R. S., Kapur, R., Zeng, L.-F., Zhang, Z.-Y., Feng, G.-S., Hartmann, K., Roers, A., Craig, A. W. B. <strong>SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice.</strong> Molec. Cell. Biol. 32: 2653-2663, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22566685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22566685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22566685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00308-12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22566685">Sharma et al. (2012)</a> generated mast cell-specific Shp2-knockout mice and found that Shp2 was required for peritoneal mast cell homeostasis. Examination of other tissues revealed reduced mature mast cells in skin, but not mucosa, of mutant mice. The results suggested that the deficit in mast cells in connective tissues was likely due to growth or survival defects within mature connective tissue mast cells (CTMCs) and not due to defects in mast cell progenitors that retained Shp2 function and allowed normal mucosal mast cell (MMC) development. Shp2 mutant mice failed to mount a mast cell IgE-mediated late-phase cutaneous reaction, unlike wildtype mice. Knockout of Shp2 in bone marrow-derived mast cells (BMMCs) showed that Shp2 promoted Scf/Kit signaling to ERK kinases and suppression of proapoptotic Bim (<a href="/entry/603827">603827</a>) in mast cells, thereby promoting BMMC survival. Further analysis revealed a significant defect in the ability of Shp2-knockout BMMCs to repopulate peritoneal mast cells and skin mast cells compared with wildtype BMMCs, demonstrating that Shp2 plays an essential role in promoting CTMC survival and homeostasis in vivo. Bim silencing in Shp2-knockout BMMCs rescued their survival defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22566685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the pathogenesis of metachondromatosis (<a href="/entry/156250">156250</a>), <a href="#55" class="mim-tip-reference" title="Yang, W., Wang, J., Moore, D. C., Liang, H., Dooner, M., Wu, Q., Terek, R., Chen, Q., Ehrlich, M. G., Quesenberry, P. J., Neel, B. G. <strong>Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling.</strong> Nature 499: 491-495, 2013. Note: Erratum: Nature 508: 420 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863940[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/nature12396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863940">Yang et al. (2013)</a> used a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages, and osteoclasts (lysozyme (<a href="/entry/153450">153450</a>) M-Cre; LysMCre) or in cathepsin K (Ctsk; <a href="/entry/601105">601105</a>)-expressing cells, theretofore thought to be osteoclasts. The LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. However, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors (Ctsk+ chondroid progenitors, or CCPs). Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh; <a href="/entry/600726">600726</a>) and parathyroid hormone-related protein (Pthrp; <a href="/entry/168470">168470</a>) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR; see <a href="/entry/136350">136350</a>) or mitogen-activated protein kinase kinase (MEK; see <a href="/entry/176872">176872</a>) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened (<a href="/entry/601500">601500</a>) inhibitor treatment ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl) mice. <a href="#55" class="mim-tip-reference" title="Yang, W., Wang, J., Moore, D. C., Liang, H., Dooner, M., Wu, Q., Terek, R., Chen, Q., Ehrlich, M. G., Quesenberry, P. J., Neel, B. G. <strong>Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling.</strong> Nature 499: 491-495, 2013. Note: Erratum: Nature 508: 420 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863940[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/nature12396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863940">Yang et al. (2013)</a> concluded that thus, in contrast to its prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23863940" 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="Coulombe, G., Leblanc, C., Cagnol, S., Maloum, F., Lemieux, E., Perrault, N., Feng, G.-S., Boudreau, F., Rivard, N. <strong>Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice.</strong> Molec. Cell. Biol. 33: 2275-2284, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23530062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23530062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23530062[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00043-13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23530062">Coulombe et al. (2013)</a> found that mice homozygous for Shp2 knockout in intestinal epithelial cells (IECs) had similar body weight to wildtype mice at birth but subsequently exhibited growth retardation. Mutant mice had diarrhea and rectal bleeding with higher mortality than wildtype mice, and macroscopic examination revealed severe colitis affecting all parts of the colon. Histologic analysis of mutant colon showed immune cell infiltration, longer crypts, and apparent reduction of goblet cells. Cytokines and chemokines were significantly upregulated in mutant mice. IEC-specific Shp2 loss deregulated intestinal permeability and decreased expression of barrier component proteins. SHP2 silencing in human Caco-2/15 cells also compromised barrier function, supporting the cell-intrinsic effect of SHP2 ablation on permeability. Western blot analysis demonstrated that IEC-specific loss of Shp2 deregulated epithelial ERK, Stat3, and NF-kappa-B (see <a href="/entry/164011">164011</a>) signaling pathways. Antibiotic treatment significantly inhibited development of colitis in mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23530062" 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="#47" class="mim-tip-reference" title="Tajan, M., Pernin-Grandjean, J., Beton, N., Gennero, I., Capilla, F., Neel, B. G., Araki, T., Valet, P., Tauber, M., Salles, J.-P., Yart, A., Edouard, T. <strong>Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth.</strong> Hum. Molec. Genet. 27: 2276-2289, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29659837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29659837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29659837[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddy133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29659837">Tajan et al. (2018)</a> found that mice heterozygous for the NS mutation D61G in SHP2 showed homogeneous postnatal growth retardation without bone deformity compared with wildtype mice. Histologic analysis revealed reduced epiphyseal growth plate length in NS mice, mostly due to shortening of the hypertrophic zone. Quantitative RT-PCR showed that the Shp2 mutant impaired chondrocyte differentiation during endochondral ossification. Further analysis demonstrated that the Shp2 mutant enhanced Ras/ERK activation in chondrocytes in vivo and in vitro. The Shp2 mutant impaired production of insulin-like growth factor-1 (IGF1; <a href="/entry/147440">147440</a>) through hyperactivation of the Ras/ERK signalling pathway, and inhibition of Ras/ERK activation was associated with significant growth improvement in NS mice. However, Igf1 supplementation only partially corrected growth retardation of NS mice, and histologic analysis of the growth plate revealed that Igf1 treatment increased the length of the proliferating zone without correcting the decreased hypertrophic zone. Statin treatment significantly improved endochondral bone growth and restored the length of the hypertrophic zone growth plate in NS mice. Moreover, statin treatment also restored alkaline phosphatase (ALPL; <a href="/entry/171760">171760</a>) expression and differentiation activity in NS mouse primary chondrocytes in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29659837" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>36 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176876[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918453 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918453;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=rs121918453" 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=rs121918453" 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=RCV000014252 OR RCV000033471 OR RCV000157001 OR RCV000212890 OR RCV000576667 OR RCV000762883 OR RCV001813190" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014252, RCV000033471, RCV000157001, RCV000212890, RCV000576667, RCV000762883, RCV001813190" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014252...</a>
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<p>In a family with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#51" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. <strong>Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.</strong> Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704759</a>] [<a href="https://doi.org/10.1038/ng772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704759">Tartaglia et al. (2001)</a> found that affected members had a G-to-T transversion at position 214 in exon 3 of the PTPN11 gene, predicting an ala72-to-ser (A72S) substitution in the N-SH2 domain. This mutation was also identified by <a href="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12161469+11704759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014253 OR RCV000157006 OR RCV000157679 OR RCV000515213 OR RCV000587329 OR RCV000707460 OR RCV001813191 OR RCV002426502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014253, RCV000157006, RCV000157679, RCV000515213, RCV000587329, RCV000707460, RCV001813191, RCV002426502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014253...</a>
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<p>In a family with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#51" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. <strong>Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.</strong> Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704759</a>] [<a href="https://doi.org/10.1038/ng772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704759">Tartaglia et al. (2001)</a> found that affected members had a C-to-G transversion at nucleotide 215 in exon 3 of the PTPN11 gene, predicting an ala72-to-gly (A72G) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704759" 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> rs28933386 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933386;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/rs28933386?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=rs28933386" 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=rs28933386" 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=RCV000014254 OR RCV000033516 OR RCV000077863 OR RCV000156977 OR RCV000515324 OR RCV000576594 OR RCV000621227 OR RCV000850589 OR RCV000999988 OR RCV001253546 OR RCV001270562 OR RCV001293867 OR RCV001813192 OR RCV003147284 OR RCV003991568 OR RCV004541002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014254, RCV000033516, RCV000077863, RCV000156977, RCV000515324, RCV000576594, RCV000621227, RCV000850589, RCV000999988, RCV001253546, RCV001270562, RCV001293867, RCV001813192, RCV003147284, RCV003991568, RCV004541002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014254...</a>
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<p>In affected members of 3 families and in a sporadic case of Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#51" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. <strong>Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.</strong> Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704759</a>] [<a href="https://doi.org/10.1038/ng772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704759">Tartaglia et al. (2001)</a> found a 922A-G transition in exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino acid change. This missense mutation affected the phosphotyrosine phosphatase (PTP) domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704759" 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 a comprehensive study of <a href="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a>, about one-third of the patients who had mutations in the PTPN11 gene had this mutation, which was by far the most common. This was the mutation present in the large 3-generation family that was used originally to establish linkage to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was further indicated by the finding of an asn308-to-ser (<a href="#0004">176876.0004</a>) missense mutation in 2 families (<a href="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al., 2002</a>). In the cohort of Noonan syndrome patients studied by <a href="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a> noted that in their cohort, no patient carrying the N308D mutation was enrolled in special education. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11992261" 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="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> found this mutation in a Japanese patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161469" 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 13 (23%) of 56 patients with Noonan syndrome, <a href="#24" class="mim-tip-reference" title="Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I. <strong>Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature.</strong> Am. J. Med. Genet. 134A: 165-170, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723289</a>] [<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15723289">Jongmans et al. (2005)</a> identified the N308D mutation, confirming the reputation of nucleotide 922 as a mutation hotspot. Among these 13 patients only 3 attended special school. Except for this suspected correlation with normal education, the phenotype observed in patients with the mutation at nucleotide 922 did not differ from the phenotype in patients with other mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15723289" 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="#56" class="mim-tip-reference" title="Yoon, S.-R., Choi, S.-K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim, N. <strong>Age-dependent germline mosaicism of the most common Noonan syndrome mutation shows the signature of germline selection.</strong> Am. J. Hum. Genet. 92: 917-926, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726368</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23726368[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726368">Yoon et al. (2013)</a> calculated that the de novo mutation frequency of the 922A-G (N308D) mutation exceeds the genome average A-G mutation frequency by more than 2,400-fold. <a href="#56" class="mim-tip-reference" title="Yoon, S.-R., Choi, S.-K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim, N. <strong>Age-dependent germline mosaicism of the most common Noonan syndrome mutation shows the signature of germline selection.</strong> Am. J. Hum. Genet. 92: 917-926, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726368</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23726368[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726368">Yoon et al. (2013)</a> examined the spacial distribution of the mutation in testes of 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be the expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2, the protein encoded by PTPN11, interacts with the transcriptional activator STAT3 (<a href="/entry/102582">102582</a>). Given STAT3's function in mouse spermatogonial stem cells, <a href="#56" class="mim-tip-reference" title="Yoon, S.-R., Choi, S.-K., Eboreime, J., Gelb, B. D., Calabrese, P., Arnheim, N. <strong>Age-dependent germline mosaicism of the most common Noonan syndrome mutation shows the signature of germline selection.</strong> Am. J. Hum. Genet. 92: 917-926, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726368</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23726368[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726368">Yoon et al. (2013)</a> suggested that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 (<a href="/entry/168461">168461</a>) might also play a role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome (<a href="/entry/101200">101200</a>) and MEN2B (<a href="/entry/162300">162300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23726368" 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">rs121918455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918455;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=rs121918455" 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=rs121918455" 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=RCV000014255 OR RCV000033518 OR RCV000037669 OR RCV000157682 OR RCV000515421 OR RCV000588570 OR RCV001027696 OR RCV001197417 OR RCV001813193 OR RCV004532339" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014255, RCV000033518, RCV000037669, RCV000157682, RCV000515421, RCV000588570, RCV001027696, RCV001197417, RCV001813193, RCV004532339" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014255...</a>
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<p>In affected members of 2 families with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a> identified an 923A-G transition in the PTPN11 gene, resulting in an asn308-to-ser (N308S) substitution. This mutation occurs in the same codon as the common N308D mutation (<a href="#0003">176876.0003</a>); thus, codon 308 is a hotspot for Noonan syndrome. One of the 2 families in which the N308S mutation was observed had typical features of Noonan syndrome associated with multiple giant cell lesions in bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11992261" 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 a case of fetal demise at 12 weeks' gestation, <a href="#4" class="mim-tip-reference" title="Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M. <strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong> Am. J. Med. Genet. 143A: 1249-1252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17497712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17497712</a>] [<a href="https://doi.org/10.1002/ajmg.a.31738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17497712">Becker et al. (2007)</a> identified compound heterozygosity for the N308S and Y63C (<a href="#0008">176876.0008</a>) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497712" 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">rs121918456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918456;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=rs121918456" 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=rs121918456" 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=RCV000030620 OR RCV000033504 OR RCV000055890 OR RCV000077859 OR RCV000492270 OR RCV000577894 OR RCV000617951 OR RCV000768062 OR RCV000824744 OR RCV001000775 OR RCV001813194 OR RCV004528108" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030620, RCV000033504, RCV000055890, RCV000077859, RCV000492270, RCV000577894, RCV000617951, RCV000768062, RCV000824744, RCV001000775, RCV001813194, RCV004528108" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030620...</a>
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<p>In 3 patients with LEOPARD syndrome-1 (LPRD1; <a href="/entry/151100">151100</a>), <a href="#14" class="mim-tip-reference" title="Digilio, M. C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B. <strong>Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.</strong> Am. J. Hum. Genet. 71: 389-394, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12058348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12058348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12058348[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/10.1086/341528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12058348">Digilio et al. (2002)</a> found an A-to-G transition at nucleotide 836 in exon 7 of the PTPN11 gene resulting in a tyr279-to-cys (Y279C) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12058348" 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="#58" class="mim-tip-reference" title="Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T. <strong>Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (Letter)</strong> Am. J. Med. Genet. 130A: 432-434, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389709</a>] [<a href="https://doi.org/10.1002/ajmg.a.30281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389709">Yoshida et al. (2004)</a> identified heterozygosity for the Y279C mutation in 2 Japanese patients with LEOPARD syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15389709" 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 a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, <a href="#2" class="mim-tip-reference" title="Alfurayh, N., Alsaif, F., Alballa, N., Zeitouni, L., Ramzan, K., Imtiaz, F., Alakeel, A. <strong>LEOPARD syndrome with PTPN11 gene mutation in three family members presenting with different phenotypes.</strong> J. Pediat. Genet. 9: 246-251, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32765928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32765928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32765928[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/10.1055/s-0039-3400226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32765928">Alfurayh et al. (2020)</a> identified the Y279C mutation. The mutation was identified by next-generation sequencing. All 3 patients had normal stature. The father had hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32765928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Edouard, T., Combier, J.-P., Nedelec, A., Bel-Vialar, S., Metrich, M., Conte-Auriol, F., Lyonnet, S., Parfait, B., Tauber, M., Salles, J.-P., Lezoualc'h, F., Yart, A., Raynal, P. <strong>Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3-beta signaling.</strong> Molec. Cell. Biol. 30: 2498-2507, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308328</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20308328[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00646-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20308328">Edouard et al. (2010)</a> found that the Y279C mutation caused elevated EGF (<a href="/entry/131530">131530</a>)-induced PI3 kinase (see <a href="/entry/601232">601232</a>)/AKT (<a href="/entry/164730">164730</a>) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (<a href="/entry/604439">604439</a>), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; <a href="/entry/171833">171833</a>). PI3 kinase hyperactivation in Y279C mutant cells also enhanced myocardin (MYOCD; <a href="/entry/606127">606127</a>)/SRF (<a href="/entry/600589">600589</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20308328" 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> rs121918457 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918457;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/rs121918457?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=rs121918457" 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=rs121918457" 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=RCV000033533 OR RCV000055884 OR RCV000077851 OR RCV000106323 OR RCV000157014 OR RCV000208002 OR RCV000515406 OR RCV000723326 OR RCV000853462 OR RCV001813197 OR RCV002390104" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033533, RCV000055884, RCV000077851, RCV000106323, RCV000157014, RCV000208002, RCV000515406, RCV000723326, RCV000853462, RCV001813197, RCV002390104" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033533...</a>
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<p>In 5 unrelated patients and in a mother-daughter pair with LEOPARD syndrome-1 (LPRD1; <a href="/entry/151100">151100</a>), <a href="#14" class="mim-tip-reference" title="Digilio, M. C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B. <strong>Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.</strong> Am. J. Hum. Genet. 71: 389-394, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12058348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12058348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12058348[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/10.1086/341528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12058348">Digilio et al. (2002)</a> found a thr468-to-met (T468M) mutation resulting from a C-to-T transition at nucleotide 1403 in exon 12 of the PTPN11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12058348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others. <strong>Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.</strong> Nature 465: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20535210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20535210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20535210[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/nature09005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20535210">Carvajal-Vergara et al. (2010)</a> generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in the PTPN11 gene. The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. <a href="#9" class="mim-tip-reference" title="Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others. <strong>Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.</strong> Nature 465: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20535210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20535210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20535210[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/nature09005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20535210">Carvajal-Vergara et al. (2010)</a> showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of NFATC4 (<a href="/entry/602699">602699</a>) in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlated with a potential hypertrophic state. <a href="#9" class="mim-tip-reference" title="Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others. <strong>Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.</strong> Nature 465: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20535210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20535210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20535210[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/nature09005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20535210">Carvajal-Vergara et al. (2010)</a> also provided molecular insights into signaling pathways that may promote the disease phenotype. <a href="#9" class="mim-tip-reference" title="Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others. <strong>Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.</strong> Nature 465: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20535210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20535210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20535210[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/nature09005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20535210">Carvajal-Vergara et al. (2010)</a> showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20535210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Edouard, T., Combier, J.-P., Nedelec, A., Bel-Vialar, S., Metrich, M., Conte-Auriol, F., Lyonnet, S., Parfait, B., Tauber, M., Salles, J.-P., Lezoualc'h, F., Yart, A., Raynal, P. <strong>Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3-beta signaling.</strong> Molec. Cell. Biol. 30: 2498-2507, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308328</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20308328[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00646-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20308328">Edouard et al. (2010)</a> found that the T468M mutation caused elevated EGF (<a href="/entry/131530">131530</a>)-induced PI3 kinase (see <a href="/entry/601232">601232</a>)/AKT (<a href="/entry/164730">164730</a>) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (<a href="/entry/604439">604439</a>), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; <a href="/entry/171833">171833</a>). PI3 kinase hyperactivation in T468M mutant cells also enhanced myocardin (MYOCD; <a href="/entry/606127">606127</a>)/SRF (<a href="/entry/600589">600589</a>) activity and promoted hypertrophic growth in cultured chicken embryo myocardial cushions and primary human cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20308328" 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 a Chinese boy (patient 3) with cafe-au-lait spots and freckles over the face and trunk, who also had dysmorphic facial features including hypertelorism, and pectus excavatum, <a href="#61" class="mim-tip-reference" title="Zhang, J., Cheng, R., Liang, J., Ni, C., Li, M., Yao, Z. <strong>Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination.</strong> Clin. Genet. 90: 372-377, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27659786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27659786</a>] [<a href="https://doi.org/10.1111/cge.12728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27659786">Zhang et al. (2016)</a> identified heterozygosity for the PTPN11 T468M mutation, which was not found in unaffected family members or in 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27659786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014260 OR RCV000033543 OR RCV000156995 OR RCV000212897 OR RCV001851849 OR RCV002490364 OR RCV004532342 OR RCV004984639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014260, RCV000033543, RCV000156995, RCV000212897, RCV001851849, RCV002490364, RCV004532342, RCV004984639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014260...</a>
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<p><a href="#32" class="mim-tip-reference" title="Maheshwari, M., Belmont, J., Fernbach, S., Ho, T., Molinari, L., Yakub, I., Yu, F., Combes, A., Towbin, J., Craigen, W. J., Gibbs, R. <strong>PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.</strong> Hum. Mutat. 20: 298-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325025</a>] [<a href="https://doi.org/10.1002/humu.10129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325025">Maheshwari et al. (2002)</a> found a de novo ser502-to-thr (S502T) substitution in exon 13 in 2 unrelated subjects with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325025" 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="#27" class="mim-tip-reference" title="Kondoh, T., Ishii, E., Aoki, Y., Shimizu, T., Zaitsu, M., Matsubara, Y., Moriuchi, H. <strong>Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report.</strong> Europ. J. Pediat. 162: 548-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12739139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12739139</a>] [<a href="https://doi.org/10.1007/s00431-003-1227-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12739139">Kondoh et al. (2003)</a> described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a Japanese infant with Noonan syndrome and the S502T mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12739139" 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> rs121918459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918459;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/rs121918459?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=rs121918459" 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=rs121918459" 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=RCV000014261 OR RCV000033468 OR RCV000077857 OR RCV000157000 OR RCV000515408 OR RCV000588678 OR RCV000722014 OR RCV001249667 OR RCV001813198 OR RCV003137518 OR RCV003147286 OR RCV004528109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014261, RCV000033468, RCV000077857, RCV000157000, RCV000515408, RCV000588678, RCV000722014, RCV001249667, RCV001813198, RCV003137518, RCV003147286, RCV004528109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014261...</a>
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<p>In 2 unrelated families, <a href="#32" class="mim-tip-reference" title="Maheshwari, M., Belmont, J., Fernbach, S., Ho, T., Molinari, L., Yakub, I., Yu, F., Combes, A., Towbin, J., Craigen, W. J., Gibbs, R. <strong>PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.</strong> Hum. Mutat. 20: 298-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325025</a>] [<a href="https://doi.org/10.1002/humu.10129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325025">Maheshwari et al. (2002)</a> found that probands with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) had a tyr63-to-cys (Y63C) mutation in exon 3. This same mutation was identified by <a href="#51" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. <strong>Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.</strong> Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704759</a>] [<a href="https://doi.org/10.1038/ng772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704759">Tartaglia et al. (2001)</a>. This mutation was also identified by <a href="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> in 2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12325025+12161469+11704759" 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>See <a href="#0004">176876.0004</a> and <a href="#4" class="mim-tip-reference" title="Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M. <strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong> Am. J. Med. Genet. 143A: 1249-1252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17497712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17497712</a>] [<a href="https://doi.org/10.1002/ajmg.a.31738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17497712">Becker et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497712" 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> rs121918460 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918460;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/rs121918460?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=rs121918460" 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=rs121918460" 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=RCV000014257 OR RCV000033466 OR RCV000153794 OR RCV000156993 OR RCV000590972 OR RCV000762882 OR RCV000824739 OR RCV001813195 OR RCV002408460 OR RCV004532340" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014257, RCV000033466, RCV000153794, RCV000156993, RCV000590972, RCV000762882, RCV000824739, RCV001813195, RCV002408460, RCV004532340" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014257...</a>
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<p>In a subject with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#32" class="mim-tip-reference" title="Maheshwari, M., Belmont, J., Fernbach, S., Ho, T., Molinari, L., Yakub, I., Yu, F., Combes, A., Towbin, J., Craigen, W. J., Gibbs, R. <strong>PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.</strong> Hum. Mutat. 20: 298-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325025</a>] [<a href="https://doi.org/10.1002/humu.10129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325025">Maheshwari et al. (2002)</a> found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene. This same mutation was identified by <a href="#49" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. <strong>PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.</strong> Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[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/10.1086/340847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992261">Tartaglia et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12325025+11992261" 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">rs121918461 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918461;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=rs121918461" 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=rs121918461" 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=RCV000014258 OR RCV000033464 OR RCV000077856 OR RCV000156984 OR RCV000626829 OR RCV000824738 OR RCV001270166 OR RCV001376030 OR RCV001813196 OR RCV002490363 OR RCV003147285 OR RCV004532341" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014258, RCV000033464, RCV000077856, RCV000156984, RCV000626829, RCV000824738, RCV001270166, RCV001376030, RCV001813196, RCV002490363, RCV003147285, RCV004532341" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014258...</a>
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<p>In a Japanese patient with sporadic Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> found an A-to-G transition at nucleotide 182 in exon 3 of the PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161469" 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">rs121918462 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918462;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=rs121918462" 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=rs121918462" 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=RCV000014262 OR RCV000033475 OR RCV000156985 OR RCV000212891 OR RCV000515312 OR RCV001813199 OR RCV002415414 OR RCV003147287 OR RCV003147288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014262, RCV000033475, RCV000156985, RCV000212891, RCV000515312, RCV001813199, RCV002415414, RCV003147287, RCV003147288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014262...</a>
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<p>In a Japanese patient with sporadic Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> identified a 218C-T transition in exon 3 of the PTPN11 gene, resulting in a thr73-to-ile (T73I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161469" 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 4 children with Noonan syndrome who developed juvenile myelomonocytic leukemia, <a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> observed a heterozygous germline T73I mutation, which alters the N-terminal Src homology 2 (SH2) domain. The T73I mutation was also identified in an individual with growth retardation, pulmonic stenosis, and JMML. Analysis of germline and parental DNAs indicated that the mutations were de novo germline events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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="#24" class="mim-tip-reference" title="Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I. <strong>Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature.</strong> Am. J. Med. Genet. 134A: 165-170, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723289</a>] [<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15723289">Jongmans et al. (2005)</a> described a patient with Noonan syndrome and mild JMML who carried the T73I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15723289" 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 a Japanese patient with sporadic Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#29" class="mim-tip-reference" title="Kosaki, K., Suzuki, T., Muroya, K., Hasegawa, T., Sato, S., Matsuo, N., Kosaki, R., Nagai, T., Hasegawa, Y., Ogata, T. <strong>PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 87: 3529-3533, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161469</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161469">Kosaki et al. (2002)</a> found a T-to-C transition at nucleotide 854 in exon 8 of the PTPN11 gene, resulting in a phe285-to-ser (F285S) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161469" 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">rs121918464 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918464;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=rs121918464" 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=rs121918464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML (<a href="/entry/607785">607785</a>) but without Noonan syndrome. A 226G-A transition predicting a glu76-to-lys (E76K) substitution within the N-SH2 domain accounted for 25% of the total number of mutations. Codon 76 was a mutation hotspot for JMML, with 4 different amino acid substitutions predicted among 8 individuals: in addition to E76K, which was present in 5 cases, E76V (<a href="#0015">176876.0015</a>), E76G (<a href="#0016">176876.0016</a>), and E76A (<a href="#0017">176876.0017</a>) were each present in 1 case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014265 OR RCV000781775 OR RCV000788241 OR RCV001813201" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014265, RCV000781775, RCV000788241, RCV001813201" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014265...</a>
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<p>See <a href="#0014">176876.0014</a> and <a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014266 OR RCV000159046 OR RCV002513040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014266, RCV000159046, RCV002513040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014266...</a>
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<p>See <a href="#0014">176876.0014</a> and <a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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">rs121918465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918465;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=rs121918465" 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=rs121918465" 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=RCV000014267 OR RCV000033477" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014267, RCV000033477" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014267...</a>
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<p>See <a href="#0014">176876.0014</a> and <a href="#52" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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">rs121918466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918466;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=rs121918466" 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=rs121918466" 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=RCV000014268 OR RCV000033480 OR RCV000037641 OR RCV000157680 OR RCV000515381 OR RCV000590740 OR RCV001813202 OR RCV002453257 OR RCV004532344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014268, RCV000033480, RCV000037641, RCV000157680, RCV000515381, RCV000590740, RCV001813202, RCV002453257, RCV004532344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014268...</a>
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<p>In 10 affected members from a large 4-generation Belgian family with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) and some features suggestive of cardiofaciocutaneous syndrome (<a href="/entry/115150">115150</a>), <a href="#43" class="mim-tip-reference" title="Schollen, E., Matthijs, G., Gewillig, M., Fryns, J.-P., Legius, E. <strong>PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.</strong> Europ. J. Hum. Genet. 11: 85-88, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529711</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529711">Schollen et al. (2003)</a> identified a 236A-G transition in exon 3 of the PTPN11 gene, resulting in a gln79-to-arg (Q79R) mutation. The mutation was not found in 7 unaffected relatives or 3 spouses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0019" class="mim-anchor"></a>
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<strong>.0019 NOONAN SYNDROME</strong>
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PTPN11, THR411MET
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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> rs121918467 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918467;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/rs121918467?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=rs121918467" 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=rs121918467" 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=RCV000014269 OR RCV001030087 OR RCV001091427 OR RCV001293768 OR RCV002362582" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014269, RCV001030087, RCV001091427, RCV001293768, RCV002362582" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014269...</a>
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<p>In a 24-year-old female with clinical features of Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) but with some characteristics of cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation, <a href="#6" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E. <strong>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.</strong> Am. J. Med. Genet. 130A: 378-383, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15384080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15384080</a>] [<a href="https://doi.org/10.1002/ajmg.a.30270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15384080">Bertola et al. (2004)</a> identified a T-to-C transition in exon 11 of the PTPN11 gene, resulting in a thr411-to-met (T411M) substitution. Molecular dynamic studies indicated that this mutation favors a more active protein conformation. The mutation was also found in the patient's mother and older sister, who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15384080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0020" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0020 LEOPARD SYNDROME 1</strong>
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PTPN11, ALA461THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918468;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=rs121918468" 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=rs121918468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033530 OR RCV000037611 OR RCV000055882 OR RCV000529342 OR RCV001002017 OR RCV001089941 OR RCV004532345" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033530, RCV000037611, RCV000055882, RCV000529342, RCV001002017, RCV001089941, RCV004532345" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033530...</a>
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<p>In a Japanese patient with LEOPARD syndrome (LPRD1; <a href="/entry/151100">151100</a>), <a href="#58" class="mim-tip-reference" title="Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T. <strong>Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (Letter)</strong> Am. J. Med. Genet. 130A: 432-434, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389709</a>] [<a href="https://doi.org/10.1002/ajmg.a.30281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389709">Yoshida et al. (2004)</a> identified heterozygosity for a 1381G-A transition in exon 12 of the PTPN11 gene, resulting in an ala461-to-thr (A461T) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15389709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0021" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0021 LEOPARD SYNDROME 1</strong>
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PTPN11, GLY464ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918469;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=rs121918469" 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=rs121918469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033531 OR RCV000055883 OR RCV000077850 OR RCV000824746 OR RCV001281363 OR RCV001813203 OR RCV002390105 OR RCV004532346" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033531, RCV000055883, RCV000077850, RCV000824746, RCV001281363, RCV001813203, RCV002390105, RCV004532346" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033531...</a>
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<p>In a Japanese patient with LEOPARD syndrome (LPRD1; <a href="/entry/151100">151100</a>), <a href="#58" class="mim-tip-reference" title="Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T. <strong>Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (Letter)</strong> Am. J. Med. Genet. 130A: 432-434, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389709</a>] [<a href="https://doi.org/10.1002/ajmg.a.30281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389709">Yoshida et al. (2004)</a> identified heterozygosity for a 1391G-C transversion in exon 12 of the PTPN11 gene, resulting in a gly464-to-ala (G464A) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15389709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0022" class="mim-anchor"></a>
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<h4>
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<strong>.0022 LEOPARD SYNDROME 1</strong>
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PTPN11, GLN510PRO
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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> rs121918470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918470;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/rs121918470?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=rs121918470" 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=rs121918470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014272 OR RCV000033554 OR RCV000210036 OR RCV000520822 OR RCV000586289 OR RCV000824752 OR RCV001254107 OR RCV002286696 OR RCV004541003" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014272, RCV000033554, RCV000210036, RCV000520822, RCV000586289, RCV000824752, RCV001254107, RCV002286696, RCV004541003" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014272...</a>
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<p>In the proband of a family with 3 individuals with LEOPARD syndrome (LPRD1; <a href="/entry/151100">151100</a>), <a href="#25" class="mim-tip-reference" title="Kalidas, K., Shaw, A. C., Crosby, A. H., Newbury-Ecob, R., Greenhalgh, L., Temple, I. K., Law, C., Patel, A., Patton, M. A., Jeffery, S. <strong>Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11.</strong> J. Hum. Genet. 50: 21-25, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15690106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15690106</a>] [<a href="https://doi.org/10.1007/s10038-004-0212-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15690106">Kalidas et al. (2005)</a> found a 1529A-C transversion in exon 13 of the PTPN11 gene resulting in a gln510-to-pro (Q510P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15690106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Edouard, T., Combier, J.-P., Nedelec, A., Bel-Vialar, S., Metrich, M., Conte-Auriol, F., Lyonnet, S., Parfait, B., Tauber, M., Salles, J.-P., Lezoualc'h, F., Yart, A., Raynal, P. <strong>Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3-beta signaling.</strong> Molec. Cell. Biol. 30: 2498-2507, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308328</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20308328[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00646-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20308328">Edouard et al. (2010)</a> found that PTPN11 with the Q510P mutation elevated EGF (<a href="/entry/131530">131530</a>)-induced PI3 kinase (see <a href="/entry/601232">601232</a>)/AKT (<a href="/entry/164730">164730</a>) phosphorylation and activation in transfected HEK293 cells compared with wildtype PTPN11. This upregulation was due to impaired dephosphorylation of GAB1 (<a href="/entry/604439">604439</a>), which enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (PIK3R1; <a href="/entry/171833">171833</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20308328" 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> rs121918470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918470;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/rs121918470?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=rs121918470" 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=rs121918470" 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=RCV000014273 OR RCV000414743 OR RCV000780654 OR RCV001002770 OR RCV004018624 OR RCV004734518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014273, RCV000414743, RCV000780654, RCV001002770, RCV004018624, RCV004734518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014273...</a>
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<p><a href="#7" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. <strong>Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong> Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>] [<a href="https://doi.org/10.1002/ajmg.a.30813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15948193">Bertola et al. (2005)</a> described a girl with both neurofibromatosis I (<a href="/entry/162200">162200</a>) and Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) who had a de novo mutation in the NF1 gene (<a href="/entry/613113#0043">613113.0043</a>) and a mutation in the PTPN11 gene inherited from her father who was mildly affected with Noonan syndrome. The PTPN11 mutation was a 1909A-G transition, resulting in a gln510-to-arg substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15948193" 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">rs121918471 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918471;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=rs121918471" 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=rs121918471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338836 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338836;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=rs80338836" 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=rs80338836" 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=RCV000014274 OR RCV002513041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014274, RCV002513041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014274...</a>
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<p>In a Japanese patient with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>), <a href="#57" class="mim-tip-reference" title="Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. <strong>Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 89: 3359-3364, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240615</a>] [<a href="https://doi.org/10.1210/jc.2003-032091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240615">Yoshida et al. (2004)</a> identified a 3-bp deletion in exon 3 of the PTPN11 gene, 181delGTG, that resulted in deletion of the gly60 codon in the N-SH2 domain of the protein. Because gly60 is directly involved in the N-SH2/PTP interaction, loss of this residue was predicted to disrupt N-SH2/PTP binding, activating the phosphatase function. <a href="#57" class="mim-tip-reference" title="Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. <strong>Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.</strong> J. Clin. Endocr. Metab. 89: 3359-3364, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240615</a>] [<a href="https://doi.org/10.1210/jc.2003-032091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240615">Yoshida et al. (2004)</a> stated that 181delGTG was the sole deletion mutation identified in the PTPN11 gene to that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014275" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014275" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014275</a>
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<p>In affected members of a 5-generation family segregating autosomal dominant metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#46" class="mim-tip-reference" title="Sobreira, N. L. M., Cirulli, E. T., Avramopoulos, D., Wohler, E., Oswald, G. L., Stevens, E. L., Ge, D., Shianna, K. V., Smith, J. P., Maia, J. M., Gumbs, C. E., Pevsner, J., Thomas, G., Valle, D., Hoover-Fong, J. E., Goldstein, D. B. <strong>Whole-genome sequencing of a single proband together with linkage analysis identifies a mendelian disease gene.</strong> PLoS Genet. 6: e1000991, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20577567[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577567">Sobreira et al. (2010)</a> identified heterozygosity for an 11-bp deletion (514del11) in exon 4 of the PTPN11 gene, predicted to cause a frameshift leading to a new sequence of 12 codons followed by a premature stop codon. Two apparently unaffected individuals who carried the deletion were found upon examination to have manifestations of the disease. The mutation was not found in 469 controls, 60% of whom were ethnically matched. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577567" 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> rs267606989 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606989;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/rs267606989?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=rs267606989" 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=rs267606989" 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=RCV000014276 OR RCV001205820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014276, RCV001205820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014276...</a>
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<p>In affected members of a 3-generation family segregating autosomal dominant metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#46" class="mim-tip-reference" title="Sobreira, N. L. M., Cirulli, E. T., Avramopoulos, D., Wohler, E., Oswald, G. L., Stevens, E. L., Ge, D., Shianna, K. V., Smith, J. P., Maia, J. M., Gumbs, C. E., Pevsner, J., Thomas, G., Valle, D., Hoover-Fong, J. E., Goldstein, D. B. <strong>Whole-genome sequencing of a single proband together with linkage analysis identifies a mendelian disease gene.</strong> PLoS Genet. 6: e1000991, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20577567[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577567">Sobreira et al. (2010)</a> identified heterozygosity for a C-to-T transition in exon 4 of the PTPN11 gene, resulting in an arg138-to-ter (R138X) substitution. A brother and sister, both parents of affected children, were unaffected carriers of the mutation, indicating incomplete penetrance. The mutation was not found in 469 controls, 60% of whom were ethnically matched. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577567" 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">rs267606990 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606990;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=rs267606990" 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=rs267606990" 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=RCV000014277 OR RCV000033445 OR RCV000211847 OR RCV000694389 OR RCV000988912 OR RCV002496356 OR RCV003156060 OR RCV004795408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014277, RCV000033445, RCV000211847, RCV000694389, RCV000988912, RCV002496356, RCV003156060, RCV004795408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014277...</a>
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<p>In a girl with both Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) and neurofibromatosis I (<a href="/entry/162200">162200</a>), <a href="#53" class="mim-tip-reference" title="Thiel, C., Wilken, M., Zenker, M., Sticht, H., Fahsold, R., Gusek-Schneider, G.-C., Rauch, A. <strong>Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.</strong> Am. J. Med. Genet. 149A: 1263-1267, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449407</a>] [<a href="https://doi.org/10.1002/ajmg.a.32837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19449407">Thiel et al. (2009)</a> found compound heterozygosity for 2 mutations: a de novo 5C-T transition in the PTPN11 gene, resulting in a thr2-to-ile (T2I) substitution, and a splice site mutation in the NF1 gene (<a href="/entry/613113#0044">613113.0044</a>). The PTPN11 mutation was predicted to destabilize the inactive form of PTPN11, resulting in increased basal activity and a gain of function. The proband had hypertelorism, low-set ears, short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. The NF1 mutation was inherited from her mother who had mild features of neurofibromatosis I. The proband's brother, who carried the heterozygous NF1 mutation, also had mild features of neurofibromatosis I. Neither the mother nor the brother had optic gliomas. However, the girl developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were also reported by <a href="#7" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. <strong>Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong> Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>] [<a href="https://doi.org/10.1002/ajmg.a.30813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15948193">Bertola et al. (2005)</a> in a patient with a combination of neurofibromatosis I and Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15948193+19449407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0028" class="mim-anchor"></a>
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<strong>.0028 METACHONDROMATOSIS</strong>
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PTPN11, 5-BP DEL, NT409
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122857 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122857;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=rs398122857" 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=rs398122857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024255" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024255" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024255</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 affected members of a family (family A) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous 5-bp deletion in exon 4 of the PTPN11 gene (409_413del5) resulting in a frameshift (Val137ArgfsTer17). The mutation was not found in an unaffected family member. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0029" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0029 METACHONDROMATOSIS</strong>
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</h4>
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<span class="mim-text-font">
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PTPN11, 11-BP DEL/24-BP INS, NT458
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122858 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122858;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=rs398122858" 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=rs398122858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024256" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024256" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024256</a>
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<span class="mim-text-font">
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<p>In 2 affected members of a family (family B) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous complex deletion/insertion mutation in exon 4 of the PTPN11 gene (458_468del11ins24), resulting in a frameshift (Thr153LysfsTer8). The mutation was not found in an unaffected family member. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 METACHONDROMATOSIS</strong>
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</h4>
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<span class="mim-text-font">
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PTPN11, 2-BP DEL, NT353
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122859 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122859;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=rs398122859" 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=rs398122859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024257</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family (family C) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous 2-bp deletion in exon 4 of the PTPN11 gene (353_354del2), resulting in a frameshift (Ser118TrpfsTer10). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 METACHONDROMATOSIS</strong>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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PTPN11, GLN506TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907157 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907157;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=rs387907157" 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=rs387907157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024258" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024258" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024258</a>
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<span class="mim-text-font">
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<p>In affected members of a family (family E) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous 1516C-T transition in exon 13 of the PTPN11 gene, resulting in a gln506-to-ter (Q506X) nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 METACHONDROMATOSIS</strong>
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</span>
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</h4>
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122860 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122860;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=rs398122860" 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=rs398122860" 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=RCV000024259" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024259" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024259</a>
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<p>In affected members of a family (family D) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous 1-bp deletion in exon 11 of the PTPN11 gene (1315del1), resulting in a frameshift (Leu439TrpfsTer33). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0033" class="mim-anchor"></a>
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<strong>.0033 METACHONDROMATOSIS</strong>
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PTPN11, IVS5AS, A-C, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122861;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=rs398122861" 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=rs398122861" 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=RCV000024260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024260</a>
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<p>In 2 affected sibs in a family (family F) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous acceptor splice site mutation in intron 5 of the PTPN11 gene (643-2A-C). The mutation was not found in either parent, including the affected mother. <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> suggested that the mother was mosaic for a PTPN11 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 METACHONDROMATOSIS</strong>
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</h4>
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PTPN11, LYS99TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907158;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=rs387907158" 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=rs387907158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024261" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024261" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024261</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family (family I) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous 295A-T transversion in exon 3 of the PTPN11 gene, resulting in a lys99-to-ter (K99X) nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 METACHONDROMATOSIS</strong>
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PTPN11, IVS9AS, G-T, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122862 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122862;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=rs398122862" 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=rs398122862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024262</a>
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<p>In an affected member of a family (family G) segregating metachondromatosis (METCDS; <a href="/entry/156250">156250</a>), <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified a heterozygous acceptor splice site mutation in intron 9 of the PTPN11 gene (1093-1G-T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0036" class="mim-anchor"></a>
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<strong>.0036 METACHONDROMATOSIS</strong>
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PTPN11, 15-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024263</a>
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<p>Using copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene, <a href="#8" class="mim-tip-reference" title="Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others. <strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong> PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533187">Bowen et al. (2011)</a> identified heterozygosity for a 15-kb deletion spanning exon 7 of the PTPN11 gene (Thr253LeufsTer54) in a patient (patient S) with metachondromatosis (METCDS; <a href="/entry/156250">156250</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21533187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Ahmad1993" class="mim-anchor"></a>
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Ahmad, S., Banville, D., Zhao, Z., Fischer, E. H., Shen, S.-H.
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<strong>A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.</strong>
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Proc. Nat. Acad. Sci. 90: 2197-2201, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308328</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20308328[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=20308328" 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/10.1128/MCB.00646-09" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2007.03.027" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.06712-11" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1067147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80938-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-004-0212-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.bjc.6605811" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00431-003-1227-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M513068200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.87.8.8694" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.emboj.7600706" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32206" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10129" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy133" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/423493" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/340847" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/499925" target="_blank">Full Text</a>]
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<strong>Purification and cloning of PZR, a binding protein and putative physiological substrate of tyrosine phosphatase SHP-2.</strong>
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J. Biol. Chem. 273: 29367-29372, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792637</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792637" 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/10.1074/jbc.273.45.29367" 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="63" class="mim-anchor"></a>
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<a id="Zheng2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zheng, J., Huang, X., Tan, W., Yu, D., Du, Z., Chang, J., Wei, L., Han, Y., Wang, C., Che, X., Zhou, Y., Miao, X., and 12 others.
|
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<strong>Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.</strong>
|
|
Nature Genet. 48: 747-757, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27213290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27213290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27213290" 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/10.1038/ng.3568" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Kelly A. Przylepa - updated : 07/06/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 04/23/2020<br>Ada Hamosh - updated : 09/05/2019<br>Marla J. F. O'Neill - updated : 03/29/2019<br>Patricia A. Hartz - updated : 08/31/2017<br>Ada Hamosh - updated : 10/03/2016<br>Patricia A. Hartz - updated : 08/17/2016<br>Ada Hamosh - updated : 10/1/2013<br>Ada Hamosh - updated : 8/26/2013<br>Patricia A. Hartz - updated : 4/19/2013<br>Nara Sobreira - updated : 5/15/2012<br>Patricia A. Hartz - updated : 4/10/2012<br>Patricia A. Hartz - updated : 3/8/2012<br>Patricia A. Hartz - updated : 2/13/2012<br>Cassandra L. Kniffin - updated : 8/1/2011<br>Cassandra L. Kniffin - updated : 11/8/2010<br>Ada Hamosh - updated : 8/20/2010<br>Marla J. F. O'Neill - updated : 6/28/2010<br>Cassandra L. Kniffin - updated : 12/29/2009<br>George E. Tiller - updated : 10/23/2009<br>Marla J. F. O'Neill - updated : 7/10/2009<br>Marla J. F. O'Neill - updated : 4/9/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Marla J. F. O'Neill - updated : 3/9/2007<br>John A. Phillips, III - updated : 11/17/2006<br>Patricia A. Hartz - updated : 10/19/2006<br>Victor A. McKusick - updated : 5/4/2006<br>Victor A. McKusick - updated : 9/21/2005<br>Cassandra L. Kniffin - updated : 6/30/2005<br>Victor A. McKusick - updated : 4/14/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Victor A. McKusick - updated : 3/7/2005<br>Marla J. F. O'Neill - updated : 1/4/2005<br>Victor A. McKusick - updated : 9/8/2004<br>Marla J. F. O'Neill - updated : 5/12/2004<br>Marla J. F. O'Neill - updated : 4/2/2004<br>Natalie E. Krasikov - updated : 3/29/2004<br>Victor A. McKusick - updated : 5/13/2003<br>John A. Phillips, III - updated : 1/21/2003<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 11/1/2002<br>Victor A. McKusick - updated : 8/16/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Ada Hamosh - updated : 1/29/2002<br>Ada Hamosh - updated : 7/20/2000<br>Ada Hamosh - updated : 3/30/2000<br>Victor A. McKusick - updated : 3/1/2000<br>Paul J. Converse - updated : 12/28/1999<br>Stylianos E. Antonarakis - updated : 4/25/1998
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 4/28/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/07/2023
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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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carol : 07/06/2023<br>mgross : 05/06/2020<br>mgross : 04/23/2020<br>carol : 09/06/2019<br>alopez : 09/05/2019<br>alopez : 03/29/2019<br>mgross : 09/01/2017<br>carol : 09/01/2017<br>mgross : 08/31/2017<br>alopez : 10/03/2016<br>mgross : 08/17/2016<br>joanna : 08/04/2016<br>carol : 04/09/2015<br>carol : 11/14/2014<br>alopez : 4/25/2014<br>mgross : 10/4/2013<br>alopez : 10/1/2013<br>alopez : 10/1/2013<br>alopez : 8/26/2013<br>mgross : 4/19/2013<br>carol : 7/27/2012<br>carol : 5/25/2012<br>mgross : 5/15/2012<br>mgross : 5/15/2012<br>terry : 5/15/2012<br>carol : 5/15/2012<br>terry : 4/10/2012<br>mgross : 3/8/2012<br>mgross : 3/8/2012<br>mgross : 2/17/2012<br>terry : 2/13/2012<br>wwang : 8/11/2011<br>ckniffin : 8/1/2011<br>wwang : 5/18/2011<br>ckniffin : 5/3/2011<br>wwang : 11/12/2010<br>ckniffin : 11/8/2010<br>wwang : 11/5/2010<br>ckniffin : 10/26/2010<br>wwang : 10/19/2010<br>ckniffin : 10/14/2010<br>wwang : 10/6/2010<br>alopez : 8/30/2010<br>terry : 8/20/2010<br>carol : 6/28/2010<br>terry : 6/28/2010<br>wwang : 1/14/2010<br>ckniffin : 12/29/2009<br>carol : 11/23/2009<br>wwang : 11/2/2009<br>terry : 10/23/2009<br>wwang : 7/22/2009<br>terry : 7/10/2009<br>wwang : 4/9/2008<br>wwang : 2/6/2008<br>terry : 2/1/2008<br>wwang : 1/8/2008<br>terry : 12/21/2007<br>wwang : 4/19/2007<br>wwang : 3/12/2007<br>terry : 3/9/2007<br>alopez : 11/17/2006<br>carol : 10/25/2006<br>terry : 10/19/2006<br>alopez : 5/4/2006<br>carol : 4/25/2006<br>carol : 4/25/2006<br>terry : 9/21/2005<br>terry : 8/3/2005<br>wwang : 7/7/2005<br>wwang : 7/5/2005<br>ckniffin : 6/30/2005<br>wwang : 4/27/2005<br>tkritzer : 4/27/2005<br>terry : 4/14/2005<br>wwang : 3/18/2005<br>terry : 3/15/2005<br>wwang : 3/9/2005<br>terry : 3/7/2005<br>carol : 1/5/2005<br>terry : 1/4/2005<br>tkritzer : 11/3/2004<br>alopez : 9/8/2004<br>terry : 9/8/2004<br>carol : 5/13/2004<br>terry : 5/12/2004<br>tkritzer : 4/5/2004<br>terry : 4/2/2004<br>tkritzer : 3/30/2004<br>terry : 3/29/2004<br>alopez : 6/3/2003<br>alopez : 5/14/2003<br>terry : 5/13/2003<br>terry : 2/24/2003<br>alopez : 1/21/2003<br>tkritzer : 11/22/2002<br>tkritzer : 11/18/2002<br>terry : 11/13/2002<br>tkritzer : 11/7/2002<br>tkritzer : 11/4/2002<br>terry : 11/1/2002<br>tkritzer : 8/23/2002<br>tkritzer : 8/21/2002<br>terry : 8/16/2002<br>alopez : 6/14/2002<br>terry : 6/12/2002<br>alopez : 1/30/2002<br>terry : 1/29/2002<br>alopez : 1/7/2002<br>alopez : 11/27/2001<br>alopez : 11/21/2001<br>alopez : 11/13/2001<br>terry : 11/12/2001<br>terry : 11/8/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/28/2000<br>terry : 7/20/2000<br>alopez : 3/31/2000<br>terry : 3/30/2000<br>alopez : 3/1/2000<br>terry : 3/1/2000<br>carol : 12/28/1999<br>alopez : 6/9/1999<br>psherman : 12/21/1998<br>terry : 11/13/1998<br>dkim : 7/23/1998<br>carol : 6/22/1998<br>terry : 6/3/1998<br>carol : 4/25/1998<br>terry : 3/26/1996<br>mark : 1/29/1996<br>jason : 7/26/1994<br>carol : 6/23/1993<br>carol : 4/28/1993
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<span class="mim-font">
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<strong>*</strong> 176876
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<h3>
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<span class="mim-font">
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PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PROTEIN-TYROSINE PHOSPHATASE 2C; PTP2C<br />
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TYROSINE PHOSPHATASE SHP2; SHP2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PTPN11</em></strong>
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<strong>SNOMEDCT:</strong> 205481009, 205684007, 205824006;
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<strong>ICD10CM:</strong> Q87.19;
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<strong>
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<em>
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Cytogenetic location: 12q24.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:112,418,947-112,509,918 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<td rowspan="4">
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<span class="mim-font">
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12q24.13
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<td>
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<span class="mim-font">
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LEOPARD syndrome 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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151100
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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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Leukemia, juvenile myelomonocytic, somatic
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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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607785
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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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</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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<td>
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<span class="mim-font">
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Metachondromatosis
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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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156250
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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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Noonan syndrome 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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163950
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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>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The protein-tyrosine phosphatases are a highly pleomorphic set of molecules that have a role in regulating the responses of eukaryotic cells to extracellular signals (Dechert et al., 1995). They achieve this by regulating the phosphotyrosine content of specific intracellular proteins. The PTPases have been grouped by virtue of the characteristic catalytic domain sequence similarities that define this family. Dechert et al. (1995) noted that the noncatalytic domain shows a striking degree of sequence heterogeneity. In general, however, mammalian PTPases can be subdivided into 1 of 2 broad categories: (1) transmembrane receptor PTPases that contain linked cytoplasmic catalytic domains, and (2) intracellular PTPases. Included within the latter category are 2 closely related mammalian intracellular PTPases whose sequences encode 2 tandem SRC homology 2 (SH2) domains that are located at the amino-terminal side of a single PTPase catalytic domain. SH2 domains enable the binding of these SH2 domain-containing PTPases to specific phosphotyrosine residues within protein sequences. The first mammalian SH2 domain-containing PTPase identified was PTP1C (PTPN6; 176883). The second mammalian SH2 domain-containing PTPase identified is encoded by the PTPN11 gene. </p>
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</span>
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<div>
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<br />
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</div>
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<strong>Cloning and Expression</strong>
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<p>Ahmad et al. (1993) isolated a cDNA encoding a nontransmembrane protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, from a human umbilical cord cDNA library. The open reading frame consists of 1,779 nucleotides potentially encoding a protein of 593 amino acids with a predicted molecular mass of 68 kD. The identity between the 2 SH2 domains of PTP2C (PTPN11) and PTP1C (PTPN6) is 50 to 60%, higher than the identity between the 2 SH2 domains within the same molecule. Unlike PTP1C, which is restricted to hematopoietic and epithelial cells, PTP2C is widely expressed in human tissues and is particularly abundant in heart, brain, and skeletal muscle. Ahmad et al. (1993) also identified a variant of PTP2C, termed PTP2Ci by them, which had an in-frame insertion of 12 basepairs within the catalytic domain. </p>
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<strong>Mapping</strong>
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<p>By fluorescence in situ hybridization, Isobe et al. (1994) mapped the PTP2C gene to 12q24.1. It is noteworthy that the PTP1C gene maps to the short arm of chromosome 12, whereas PTP2C maps to the long arm. Dechert et al. (1995) used a 2.1-kb SH-PTP2 cDNA clone (Bastien et al., 1993) to localize the PTPN11 gene to 12q24.1-q24.3 by isotopic in situ hybridization. The presence of cross-hybridizing sequences located on a number of other chromosomes suggested that latent genes or pseudogenes are present in the human genome. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Hof et al. (1998) described the crystal structure of amino acid residues 1 to 527 of the PTPN11 protein at 2.0-angstrom resolution. The crystal structure showed how its catalytic activity is regulated by its two SH2 domains. In the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain binds the phosphatase domain and directly blocks its active site. This interaction alters the structure of the N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely, interaction of the N-SH2 domain with phosphopeptide disrupts its phosphatase recognition surface. Thus, the N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-terminal SH2 domain contributes binding energy and specificity, but does not have a direct role in activation. </p><p>Reduction of SHP2 activity suppresses tumor cell growth and is a potential target of cancer therapy. Chen et al. (2016) reported the discovery of a highly potent (IC50 = 0.071 micromolar), selective, and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an autoinhibited conformation. The crystal structure of SHP099 in complex with to SHP2 at 1.7-angstrom resolution showed that SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppressed RAS-ERK signaling to inhibit the proliferation of receptor tyrosine kinase-driven human cancer cells in vitro and was efficacious in mouse tumor xenograft models. Chen et al. (2016) concluded that pharmacologic inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers. </p>
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<strong>Gene Function</strong>
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<p>Zhao and Zhao (1998) presented evidence indicating that MPZL1 (604376) and PTPNS1 (602461) are substrates for PTPN11. </p><p>Using wildtype and Shp2 -/- mouse embryonic fibroblasts, Zannettino et al. (2003) found that full-length human PZR (MPZL1), which contains 2 intracellular Shp2-binding immunoreceptor tyrosine-based inhibitory motifs (ITIMs), promoted Shp2-dependent migration over a fibronectin (FN1; 135600) substrate. PZR isoforms lacking the intracellular ITIMs did not promote Shp2-dependent cell migration. </p><p>Helicobacter pylori CagA protein is injected from the attached H. pylori into host cells in the stomach and undergoes tyrosine phosphorylation. Higashi et al. (2002) demonstrated that wildtype but not phosphorylation-resistant CagA induces a growth factor-like response in gastric epithelial cells by forming a physical complex with SHP2 in a phosphorylation-dependent manner and stimulating the phosphatase activity. Disruption of the CagA-SHP2 complex abolishes the CagA-dependent cellular response. Conversely, the CagA effect on cells was reproduced by constitutively active SHP2. Thus, Higashi et al. (2002) concluded that upon translocation, CagA perturbs cellular functions by deregulating SHP2. </p><p>Kwon et al. (2005) showed that activation of T-cell antigen receptor (see 186880) in human Jurkat T cells and in mouse T-cell blasts induced transient inactivation of SHP2 by the oxidation of the SHP2 active site cysteine. SHP2 was recruited to the LAT (602354)-GADS (GRAP2; 604518)-SLP76 (LCP2; 601603) complex and regulated the phosphorylation of VAV1 (164875) and ADAP (FYB; 602731). The association of ADAP with the SLP76 complex was regulated by SHP2 in a redox-dependent manner. Kwon et al. (2005) concluded that TCR-mediated ROS generation leads to SHP2 oxidation, which promotes T-cell adhesion through effects on SLP76-dependent signaling. </p><p>Kikkawa et al. (2010) identified a putative microRNA-489 (MIR489; 614523) target site in the 3-prime UTR of PTPN11, which encodes a protein tyrosine phosphatase that can activate RAS (HRAS; 190020)-MAP kinase (see 176948) signaling in response to growth factors and cytokines. Overexpression of MIR489 in a human squamous cell carcinoma cell line reduced PTPN11 mRNA and protein expression and inhibited expression of a reporter gene containing a partial PTPN11 3-prime UTR. PTPN11 mRNA expression was significantly higher in hypopharyngeal squamous cell carcinomas compared with adjacent normal tissue from 16 patients. In contrast, MIR489 was downregulated in hypopharyngeal squamous cell carcinomas. </p><p>Using RNA pull-down assays and mass spectrometric analysis, Zheng et al. (2016) found that the long intergenic noncoding RNA LINC00673 (617079) interacted with PTPN11, which promotes cell growth and proliferation by activating SRC (190090)-ERK (see 176948) signaling and inhibiting STAT1 (600555) signaling. RNA immunoprecipitation assays confirmed interaction of PTPN11 with LINC00673, which promoted ubiquitination and degradation of PTPN11. LINC00673 interacted with the E3 ubiquitin ligase PRPF19 (608330) and appeared to mediate and strengthen the interaction between PTPN11 and PRPF19, enhancing PRPF19-mediated ubiquitination and degradation of PTPN11. Zheng et al. (2016) concluded that LINC00673 plays a role in maintenance of cellular homeostasis by regulating PTPN11. </p><p>Dong et al. (2016) reported that Ptpn11 activating mutations in the mouse bone marrow microenvironment promoted the development and progression of myeloproliferative neoplasm (MPN) through profound detrimental effects on hematopoietic stem cells. Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, caused excessive production of the CC chemokine CCL3 (182283), which recruited monocytes to the area in which hematopoietic stem cells also resided. Consequently, hematopoietic stem cells were hyperactivated by interleukin-1-beta (IL1B; 147720) and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reversed MPN development induced by the Ptpn11-mutated bone marrow microenvironment. Dong et al. (2016) concluded that their study revealed the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukemogenesis and identified CCL3 as a potential therapeutic target for controlling leukemic progression in Noonan syndrome (163950) and for improving stem cell transplantation therapy in Noonan syndrome-associated leukemias. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Noonan Syndrome 1</em></strong></p><p>
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In more than 50% of patients with Noonan syndrome (see NS1, 163950), Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP-2 activity underlie the pathogenesis of Noonan syndrome. </p><p>Tartaglia et al. (2002) identified a PTPN11 mutation (176876.0004) in a family inheriting Noonan syndrome with multiple giant cell lesions in bone. </p><p>Using direct DNA sequencing, Maheshwari et al. (2002) surveyed 16 subjects with the clinical diagnosis of Noonan syndrome from 12 families and their relevant family members for mutations in the PTPN11/SHP2 gene, and found 3 different mutations among 5 families. Two unrelated subjects shared a de novo ser502-to-thr (S502T; 176876.0007) substitution in exon 13; 2 additional unrelated families had a tyr63-to-cys (Y63C; 176876.0008) mutation in exon 3; and 1 subject had a tyr62-to-asp (Y62D; 176876.0009) substitution, also in exon 3. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N-terminal SH2 domain and the phosphatase catalytic domain. Six of 8 subjects with mutations had pulmonary valve stenosis, while no mutations were identified in 4 subjects with hypertrophic cardiomyopathy. An additional 4 subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11 were identified. These results confirmed that mutations in PTPN11 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 gives rise to Noonan syndrome. </p><p>Kosaki et al. (2002) analyzed the PTPN11 gene in 21 Japanese patients with Noonan syndrome. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed 6 different heterozygous missense mutations in 7 cases. The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. </p><p>Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients. They identified 15 mutations, all of which were missense mutations; 11 of them were located in exon 3, which encodes the N-SH2 domain. No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of the patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the group of 64 patients without PTPN11 mutations suggested further genetic heterogeneity. </p><p>Tartaglia et al. (2004) investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in Noonan syndrome. By analyzing intronic positions that flank the exonic PTPN11 lesions in 49 sporadic Noonan syndrome cases, they traced the parental origin of mutations in 14 families. All mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. They also found advanced paternal age among cohorts of sporadic Noonan syndrome cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic Noonan syndrome caused by PTPN11 mutations, as well as in families inheriting the disorder. They favored sex-specific developmental effects as the explanation for the sex-ratio distortion in PTPN11-associated Noonan syndrome, because fetal lethality has been documented in this disorder. </p><p>Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18 patients. </p><p>Becker et al. (2007) reported what they stated was the first known case of compound heterozygosity for NS-causing mutations in the PTPN11 gene (see 176876.0004 and 176876.0008), resulting in early fetal death. </p><p>Shchelochkov et al. (2008) and Graham et al. (2009) reported 2 unrelated patients with a Noonan syndrome phenotype associated with respective 10-Mb and 8.98-Mb duplications on chromosome 12q24.13, encompassing the PTPN11 gene. Graham et al. (2009) did not identify additional duplications in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. Graham et al. (2009) concluded that duplication of PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling. </p><p>Patients affected with cardiofaciocutaneous syndrome (CFC; 115150) present with symptoms that some considered to represent a more severe expression of Noonan syndrome, namely, congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. Because mutations in PTPN11 are responsible for Noonan syndrome, Ion et al. (2002) investigated the possibility that this gene may be involved in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC 'based on OMIM diagnostic criteria' was examined for mutations in the PTPN11 coding sequence by means of denaturing high-performance liquid chromatography (DHPLC). No abnormalities in the coding region of the gene were found in any patient, nor any evidence of major deletions within the gene. Musante et al. (2003) screened for mutations in the PTPN11 gene in 5 sporadic patients with CFC syndrome and found none. </p><p>In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses. The authors noted that in D. melanogaster and C. elegans, the Ptpn11 gene has been implicated in oogenesis. In this family, there were 3 sets of dizygotic twins among the offspring of 2 affected females, suggesting that PTPN11 might also be involved in oogenesis and twinning in humans. </p><p>Bertola et al. (2004) described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement, developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (176876.0019); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. </p><p><strong><em>LEOPARD Syndrome 1</em></strong></p><p>
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LEOPARD syndrome (LPRD1; 151100) is an autosomal dominant disorder characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects, sharing several clinical features with Noonan syndrome. Digilio et al. (2002) screened 9 patients with LEOPARD syndrome (including a mother-daughter pair), and 2 children with Noonan syndrome who had multiple cafe-au-lait spots, for mutations in the PTPN11 gene. In 10 of the 11 patients, they found 1 of 2 novel missense mutations: Y27C (176876.0005) in exon 7 or T468M (176876.0006) in exon 12. Both mutations affected the PTPN11 phosphotyrosine phosphatase domain, which is involved in less than 30% of the Noonan syndrome PTPN11 mutations. This study demonstrated that LEOPARD syndrome and Noonan syndrome are allelic disorders. The detected mutations suggested that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the LEOPARD syndrome subtype of Noonan syndrome. </p><p>Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. </p><p>In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004) identified 1 of 3 heterozygous missense mutations: tyr279 to cys (Y279C), ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021). </p><p>In a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, Alfurayh et al. (2020) identified heterozygosity for the Y279C mutation (176876.0005) in the PTPN11 gene. The mutation was identified by next-generation sequencing. The father had normal stature, hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, normal stature, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect. </p><p><strong><em>Juvenile Myelomonocytic Leukemia</em></strong></p><p>
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Juvenile myelomonocytic leukemia (JMML; 607785), a disorder with excessive proliferation of myelomonocytic cells, constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. JMML is observed occasionally in patients with Noonan syndrome, leading Tartaglia et al. (2003) to consider whether defects in PTPN11 are present in myeloid disorders. In 5 unrelated children with Noonan syndrome and JMML, they found heterozygosity with respect to a mutation in exon 3 of PTPN11. Four of the children shared the same mutation (218C-T; 176876.0011). In 2 unrelated individuals with growth retardation, pulmonic stenosis, and JMML, they found missense defects in PTPN11: the 218C-T transition, and a defect in exon 13 affecting the protein tyrosine phosphatase domain. Analysis of germline and parental DNAs for these 6 cases indicated that the mutations were de novo germline events. </p><p>Tartaglia et al. (2003) also identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML but without Noonan syndrome, with 9 different molecular defects in exon 3 and 1 in exon 13. Nonhematologic DNAs were available for 9 individuals with a mutation in PTPN11 in their leukemic cells, and none harbored the defect. </p><p>Tartaglia et al. (2003) identified no mutation in PTPN11 among 8 individuals with JMML and neurofibromatosis type I (162200). Molecular screening for mutations in exons 1 and 2 of NRAS (164790) and KRAS2 (190070) identified defects in 5 and 7 individuals with isolated cases of JMML, respectively, none of whom harbored a mutation in PTPN11. This indicated that defects in RAS, neurofibromin, and SHP2, all involved in regulation of the MAPK cascade, are mutually exclusive in JMML. Comparison of phenotypes and karyotypes did not identify differences between individuals with JMML who did or did not have mutations in PTPN11. </p><p><strong><em>Other Malignancies</em></strong></p><p>
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Tartaglia et al. (2003) investigated the prevalence of somatic mutations in PTPN11 among 50 children with myelodysplastic syndrome. They identified no mutation among 23 children with refractory anemia, but observed missense mutations in exon 3 in 5 of 27 children with an excess of blasts. Three of these mutations were also associated with JMML in other patients. Among 24 children with de novo AML (601626), they identified a novel trinucleotide substitution in an infant with acute monoblastic leukemia. </p><p>Bentires-Alj et al. (2004) demonstrated that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma (256700) and AML. </p><p><strong><em>Metachondromatosis</em></strong></p><p>
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Using whole-genome sequencing in 1 affected individual from a 5-generation family with metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified a heterozygous 11-bp deletion in the PTPN11 gene (176876.0025) that segregated with the disease. Sequencing of PTPN11 in another family with metachondromatosis revealed a heterozygous nonsense mutation (176876.0026) in affected individuals. Neither mutation was detected in 469 controls. </p><p>Bowen et al. (2011) used a targeted array to capture exons and promoter sequences from an 8.6-Mb linked interval in 16 participants from 11 metachondromatosis families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. By this method, they identified heterozygous putative loss-of-function mutations in the PTPN11 gene in 4 of the 11 families (176876.0028-176876.0031). Sanger sequence analysis of PTPN11 coding regions in the 7 remaining families and in 6 additional metachondromatosis families identified novel heterozygous mutations in 4 families (176876.0032-176876.0035). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an METCDS patient with a 15-kb deletion spanning exon 7 of PTPN11 (176876.0036). In total, of 17 METCDS families, Bowen et al. (2011) identified mutations in 11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each family had a different mutation, and the mutations were scattered across the gene. Microdissected METCDS lesions from 2 patients with PTPN11 mutations demonstrated loss of heterozygosity for the wildtype allele. Bowen et al. (2011) suggested that metachondromatosis may be genetically heterogeneous because 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Tartaglia et al. (2002) reported the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. They found mutations in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense and several were recurrent. Pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them: 70.6% vs 46.2% (P less than 0.01); hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations: 5.9% vs 26.2%; (P less than 0.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the 2 groups. A PTPN11 mutation was identified in a family inheriting Noonan syndrome with multiple giant cell lesions in bone, extending the phenotypic range of disease associated with this gene (see 176876.0004). </p><p>Sarkozy et al. (2003) analyzed the PTPN11 gene in 71 Italian patients with Noonan syndrome and 13 with multiple lentigines/LEOPARD syndrome (ML/LS) and identified 14 different missense mutations in 34 patients, 23 with Noonan syndrome and 11 with ML/LS. The distribution of congenital heart defects was markedly different between the 2 groups. Pulmonary valve stenosis, the most common congenital heart defect in Noonan syndrome, was related to an exon 8 mutation hotspot at residue asn308 (see, e.g., 176876.0003 and 176876.0004), whereas hypertrophic cardiomyopathy, predominant in patients with ML/LS, was associated with mutations in exon 7 (see, e.g., Y279C, 176876.0005) and exon 12 (see, e.g., T468M, 176876.0006). Atrial septal defects were related to exon 3 mutations (see, e.g., Y62D, 176876.0009), whereas atrioventricular canal defects and mitral valve anomalies were found in association with different exon mutations. </p><p>Niihori et al. (2005) identified PTPN11 mutations in 16 of 41 patients with Noonan syndrome and 3 of 29 patients with childhood leukemia. Immune complex tyrosine phosphatase assays showed that all the mutations resulted in increased phosphatase activity compared to wildtype. Several mutations in the N-SH2 domain, including T73I (176876.0011), showed a 6- to 12-fold increase in activity. Other N-SH2 mutations (Y63C; 176876.0008 and Q79R; 176876.0018) and PTP-domain mutations (N308D; 176876.0003 and S502T; 176876.0007) showed a 2- to 4-fold increase in activity. These results and a review of previously reported cases indicated that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis. Two mutations associated with Noonan syndrome failed to promote the RAS/MAPK downstream signaling pathway. </p><p>Tartaglia et al. (2006) proposed a model that splits Noonan syndrome- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, they investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP2 proteins recurring in Noonan syndrome, LEOPARD syndrome, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that Noonan syndrome-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. Furthermore, they showed that the recurrent LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid substitutions engender loss of SHP2 catalytic activity, identifying a previously unrecognized behavior of this class of missense PTPN11 mutations. By molecular modeling and biochemical studies, Kontaridis et al. (2006) showed that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. They concluded that pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. </p><p>Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. They identified 11 mutations in 18 patients. Clinical assessment showed that the growth pattern was similar in mutation-positive and mutation-negative patients. Pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients, as was atrial septal defect, whereas hypertrophic cardiomyopathy was present in 5 mutation-negative patients only. Hematologic abnormalities such as bleeding diathesis and juvenile myelomonocytic leukemia were exclusively present in mutation-positive patients. </p><p>Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene (164760), and 6 in whom no mutation had been found. Patients without PTPN11 mutations showed a significantly higher frequency of family history of sudden death, increased left atrial dimensions, and cardiac arrhythmias, and seemed to be at higher risk for adverse cardiac events. Three patients with mutations in exon 13 of the PTPN11 gene had a severe form of biventricular obstructive LVH with early onset of heart failure symptoms, consistent with previous observations. </p>
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<strong>Animal Model</strong>
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<p>Atrioventricular and semilunar valve abnormalities are common birth defects. During studies of genetic interaction between Egr2 and Ptpn11, encoding the protein-tyrosine phosphatase Shp2, Chen et al. (2000) found that Egfr (131550) is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele 'waved-2' exhibited semilunar valve enlargement resulting from overabundant mesenchymal cells. Egfr -/- mice (on CD1 background) had similar defects. The penetrance and severity of the defects in the homozygous 'waved-2' mice were enhanced by heterozygosity for targeted mutation of exon 2 of Ptpn11. Compound mutant mice also showed premature lethality. Electrocardiography, echocardiography, and hemodynamic analyses showed that affected mice developed aortic stenosis and regurgitation. The results identified Egfr and Shp2 as components of a growth-factor signaling pathway required specifically for semilunar valvulogenesis, supported the hypothesis that Shp2 is required for Egfr signaling in vivo, and provided an animal model for aortic valve disease. </p><p>Shp2 can potentiate signaling for the MAP kinase pathway (see 602425) and is required during early mouse development for gastrulation. Chimeric analysis can identify, by study of phenotypically normal embryos, tissues that tolerate mutant cells, and therefore do not require the mutated gene, or lack mutant cells and presumably require the mutated gene during the developmental history. Saxton et al. (2000) therefore generated chimeric mouse embryos to explore the cellular requirements for Shp2. This analysis revealed an obligatory role for Shp2 during outgrowth of the limb. Shp2 is specifically required in mesenchyme cells of the progress zone, directly beneath the distal ectoderm of the limb bud. Comparison of Ptpn11 mutant and Fgfr1 (136350) mutant chimeric limbs indicated that in both cases mutant cells failed to contribute to the progress zone of phenotypically normal chimeras, leading to the hypothesis that a signal transduction pathway, initiated by Fgfr1 and acting through Shp2, is essential within progress zone cells. Rather than integrating proliferative signals, Shp2 probably exerts its effects on limb development by influencing cell shape, movement, or adhesion. Furthermore, the branchial arches, which also use Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates phosphotyrosine-signaling events during the complex ectodermal-mesenchymal interactions that regulate mammalian budding morphogenesis. </p><p>Saxton et al. (1997) generated mice deficient in Shp2 by targeted disruption. Homozygous Shp2 -/- mice die at midgestation with multiple defects in mesodermal patterning, while heterozygous mutants appear normal. Qu et al. (1998) aggregated homozygous mutant embryonic stem (ES) cells and wildtype embryos to create Shp2 -/- wildtype chimeric animals. They reported an essential role of Shp2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp2 -/- progenitors for erythroid or myeloid cells were detected in the fetal liver or bone marrow of chimeric animals by using the in vitro colony forming unit (CFU) assay. Furthermore, hematopoiesis was defective in Shp2 -/- yolk sacs. In addition, the Shp2 mutant caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathologic changes in the lungs, intestines, and skin. Qu et al. (1998) concluded that Shp2 is involved in the differentiation of multiple tissue-specific cells and in body organization. They suggested that the requirement for Shp2 appears to be more stringent in hematopoiesis than in other systems. </p><p>Using mouse and zebrafish models, Paardekooper Overman et al. (2014) found that both Shp2 activating mutations associated with Noonan syndrome and Shp2 inactivating mutations associated with LEOPARD syndrome caused tyrosine hyperphosphorylation of Pzr. Immunoprecipitation analysis indicated that the mutations, which result in an open Shp2 conformation, increased association of the tyrosine kinase Src (190090) with Shp2 and Pzr, suggesting a pathway for Pzr hyperphosphorylation. </p><p>Zhang et al. (2004) selectively deleted Shp2 in postmitotic forebrain neurons of mice and observed the development of early-onset obesity with increased serum levels of leptin (164160), insulin (176730), glucose, and triglycerides, although the mutant mice were not hyperphagic. In wildtype mice, the authors found that Shp2 downregulation of Jak2 (147796)/Stat3 (102582) activation by leptin in the hypothalamus was offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see 601795) pathway; thus, Shp2 deletion in the brain results in induction rather than suppression of leptin resistance. Zhang et al. (2004) suggested that a primary function of SHP2 in the postmitotic forebrain is to control energy balance and metabolism, and that SHP2 is a critical signaling component of the leptin receptor (601007) in the hypothalamus. </p><p>Using a constitutively active mouse Shp2 mutant, He et al. (2012) found that Shp2 integrated leptin and estrogen signaling in transgenic female mice. Transgenic females, but not males, were resistant to high-fat diet-induced obesity and liver steatosis via enhanced leptin and insulin sensitivity and downstream ERK activation. SHP2 and estrogen receptor-alpha (ESR1; 133430) interacted directly in MCF-7 cells and female mouse tissues, and the interaction was enhanced by estrogen stimulation. Ovariectomy of transgenic mice reversed their resistance to high-fat diet-induced obesity. </p><p>Nakamura et al. (2007) generated Q79R (176876.0018) transgenic mice in which the mutated protein was expressed in cardiomyocytes either during gestation or following birth. Q79R Shp2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, whereas in the postnatal cardiomyocyte, Q79R Shp2 expression was benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway (see 176948), and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2. Nakamura et al. (2007) concluded that there are developmental stage-specific effects of Q79R cardiac expression in Noonan syndrome, and that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities. </p><p>In cultured mouse embryonic cortical precursor cells, Gauthier et al. (2007) found that Shp2 enhanced neurogenesis and inhibited cytokine-mediated astrocytosis. Inhibition of Shp2 resulted in decreased neurogenesis, aberrant migration of neurons, and premature gliogenesis. Expression of a Noonan syndrome-associated Shp2 mutant with enhanced activity promoted neurogenesis and inhibited astrogenesis in vitro and in vivo. Further studies showed that Shp2 promotes neurogenesis via activation of the MEK-ERK pathway, and inhibits gliogenesis by suppressing the gp130 (IL6ST; 600694)-JAK-STAT pathway. Gauthier et al. (2007) suggesting that the cognitive impairment observed in some patients with Noonan syndrome may result from aberrant neuron cell-fate and a perturbation in the relative ratios of these brain cell types during development. </p><p>To study the developmental effects of the Y279C and T468M mutations in the PTPN11 gene, Oishi et al. (2009) generated the equivalent mutations in the orthologous Drosophila corkscrew (csw) gene. Ubiquitous expression of the mutant csw alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were gain-of-function phenotypes mediated by increased RAS/MAPK signaling and requiring the residual phosphatase activity of the mutant Y279C and T468M alleles. </p><p>Princen et al. (2009) created mice with deletion of Shp2 directed to striated muscle. Homozygous mutant mice were born at the expected frequency, but developed severe dilated cardiomyopathy, resulting in heart failure and death within 2 weeks of birth. Development of cardiomyopathy was associated with insulin resistance, glucose intolerance, and impaired insulin-stimulated glucose uptake in striated muscle. No significant abnormalities were observed in other tissues and organs, including skeletal muscle. </p><p>Xu et al. (2010) found that mice with a germline heterozygous D61G mutation (176876.0010) developed a JMML-like myeloproliferative disorder with excessive myeloid expansion in the bone marrow and spleen. Homozygous mutant mice were embryonic lethal due to cardiac developmental defects. Heterozygous mutant mice had higher levels of short- and long-term hematopoietic stem cells in the bone marrow and spleen compared to wildtype mice. Stem cells from heterozygous mutant mice showed enhanced entry of quiescent stem cells (G0 phase) into the cell cycle, as well as decreased apoptosis, and showed a greater long-term repopulating ability in transplanted mice compared to wildtype cells. Primary and secondary recipient mice transplanted with D61G-mutant bone marrow cells or purified lineage-negative Sca1+/Kit+ (LSK) cells developed a myeloproliferative disorder, suggesting that the pathogenic effects of the Ptpn11 mutation are cell autonomous and occur at the level of the hematopoietic stem cell. D61G-mutant cells also showed an enhanced response to stimulation with IL3 (147740). Studies with heterozygous D61G/Gab2 (606203)-null mice and cells showed attenuation of the increased number of stem cells, indicating that Gab2 is an important mediator of the myeloproliferative disorder induced by the D61G mutation. Gab2 is a prominent PTPN11-interacting protein with a role in cell signaling. </p><p>Sharma et al. (2012) generated mast cell-specific Shp2-knockout mice and found that Shp2 was required for peritoneal mast cell homeostasis. Examination of other tissues revealed reduced mature mast cells in skin, but not mucosa, of mutant mice. The results suggested that the deficit in mast cells in connective tissues was likely due to growth or survival defects within mature connective tissue mast cells (CTMCs) and not due to defects in mast cell progenitors that retained Shp2 function and allowed normal mucosal mast cell (MMC) development. Shp2 mutant mice failed to mount a mast cell IgE-mediated late-phase cutaneous reaction, unlike wildtype mice. Knockout of Shp2 in bone marrow-derived mast cells (BMMCs) showed that Shp2 promoted Scf/Kit signaling to ERK kinases and suppression of proapoptotic Bim (603827) in mast cells, thereby promoting BMMC survival. Further analysis revealed a significant defect in the ability of Shp2-knockout BMMCs to repopulate peritoneal mast cells and skin mast cells compared with wildtype BMMCs, demonstrating that Shp2 plays an essential role in promoting CTMC survival and homeostasis in vivo. Bim silencing in Shp2-knockout BMMCs rescued their survival defects. </p><p>To investigate the pathogenesis of metachondromatosis (156250), Yang et al. (2013) used a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages, and osteoclasts (lysozyme (153450) M-Cre; LysMCre) or in cathepsin K (Ctsk; 601105)-expressing cells, theretofore thought to be osteoclasts. The LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. However, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors (Ctsk+ chondroid progenitors, or CCPs). Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh; 600726) and parathyroid hormone-related protein (Pthrp; 168470) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR; see 136350) or mitogen-activated protein kinase kinase (MEK; see 176872) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened (601500) inhibitor treatment ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl) mice. Yang et al. (2013) concluded that thus, in contrast to its prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production. </p><p>Coulombe et al. (2013) found that mice homozygous for Shp2 knockout in intestinal epithelial cells (IECs) had similar body weight to wildtype mice at birth but subsequently exhibited growth retardation. Mutant mice had diarrhea and rectal bleeding with higher mortality than wildtype mice, and macroscopic examination revealed severe colitis affecting all parts of the colon. Histologic analysis of mutant colon showed immune cell infiltration, longer crypts, and apparent reduction of goblet cells. Cytokines and chemokines were significantly upregulated in mutant mice. IEC-specific Shp2 loss deregulated intestinal permeability and decreased expression of barrier component proteins. SHP2 silencing in human Caco-2/15 cells also compromised barrier function, supporting the cell-intrinsic effect of SHP2 ablation on permeability. Western blot analysis demonstrated that IEC-specific loss of Shp2 deregulated epithelial ERK, Stat3, and NF-kappa-B (see 164011) signaling pathways. Antibiotic treatment significantly inhibited development of colitis in mutant mice. </p><p>Tajan et al. (2018) found that mice heterozygous for the NS mutation D61G in SHP2 showed homogeneous postnatal growth retardation without bone deformity compared with wildtype mice. Histologic analysis revealed reduced epiphyseal growth plate length in NS mice, mostly due to shortening of the hypertrophic zone. Quantitative RT-PCR showed that the Shp2 mutant impaired chondrocyte differentiation during endochondral ossification. Further analysis demonstrated that the Shp2 mutant enhanced Ras/ERK activation in chondrocytes in vivo and in vitro. The Shp2 mutant impaired production of insulin-like growth factor-1 (IGF1; 147440) through hyperactivation of the Ras/ERK signalling pathway, and inhibition of Ras/ERK activation was associated with significant growth improvement in NS mice. However, Igf1 supplementation only partially corrected growth retardation of NS mice, and histologic analysis of the growth plate revealed that Igf1 treatment increased the length of the proliferating zone without correcting the decreased hypertrophic zone. Statin treatment significantly improved endochondral bone growth and restored the length of the hypertrophic zone growth plate in NS mice. Moreover, statin treatment also restored alkaline phosphatase (ALPL; 171760) expression and differentiation activity in NS mouse primary chondrocytes in vitro. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>36 Selected Examples):</strong>
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<strong>.0001 NOONAN SYNDROME 1</strong>
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PTPN11, ALA72SER
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SNP: rs121918453,
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ClinVar: RCV000014252, RCV000033471, RCV000157001, RCV000212890, RCV000576667, RCV000762883, RCV001813190
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<p>In a family with Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found that affected members had a G-to-T transversion at position 214 in exon 3 of the PTPN11 gene, predicting an ala72-to-ser (A72S) substitution in the N-SH2 domain. This mutation was also identified by Kosaki et al. (2002). </p>
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<strong>.0002 NOONAN SYNDROME 1</strong>
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PTPN11, ALA72GLY
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SNP: rs121918454,
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ClinVar: RCV000014253, RCV000157006, RCV000157679, RCV000515213, RCV000587329, RCV000707460, RCV001813191, RCV002426502
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<p>In a family with Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found that affected members had a C-to-G transversion at nucleotide 215 in exon 3 of the PTPN11 gene, predicting an ala72-to-gly (A72G) amino acid substitution. </p>
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<strong>.0003 NOONAN SYNDROME 1</strong>
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PTPN11, ASN308ASP
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SNP: rs28933386,
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gnomAD: rs28933386,
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ClinVar: RCV000014254, RCV000033516, RCV000077863, RCV000156977, RCV000515324, RCV000576594, RCV000621227, RCV000850589, RCV000999988, RCV001253546, RCV001270562, RCV001293867, RCV001813192, RCV003147284, RCV003991568, RCV004541002
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<p>In affected members of 3 families and in a sporadic case of Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found a 922A-G transition in exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino acid change. This missense mutation affected the phosphotyrosine phosphatase (PTP) domain. </p><p>In a comprehensive study of Tartaglia et al. (2002), about one-third of the patients who had mutations in the PTPN11 gene had this mutation, which was by far the most common. This was the mutation present in the large 3-generation family that was used originally to establish linkage to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was further indicated by the finding of an asn308-to-ser (176876.0004) missense mutation in 2 families (Tartaglia et al., 2002). In the cohort of Noonan syndrome patients studied by Tartaglia et al. (2002) noted that in their cohort, no patient carrying the N308D mutation was enrolled in special education. </p><p>Kosaki et al. (2002) found this mutation in a Japanese patient. </p><p>In 13 (23%) of 56 patients with Noonan syndrome, Jongmans et al. (2005) identified the N308D mutation, confirming the reputation of nucleotide 922 as a mutation hotspot. Among these 13 patients only 3 attended special school. Except for this suspected correlation with normal education, the phenotype observed in patients with the mutation at nucleotide 922 did not differ from the phenotype in patients with other mutations. </p><p>Yoon et al. (2013) calculated that the de novo mutation frequency of the 922A-G (N308D) mutation exceeds the genome average A-G mutation frequency by more than 2,400-fold. Yoon et al. (2013) examined the spacial distribution of the mutation in testes of 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be the expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2, the protein encoded by PTPN11, interacts with the transcriptional activator STAT3 (102582). Given STAT3's function in mouse spermatogonial stem cells, Yoon et al. (2013) suggested that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 (168461) might also play a role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome (101200) and MEN2B (162300). </p>
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<span class="mim-font">
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<strong>.0004 NOONAN SYNDROME 1</strong>
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PTPN11, ASN308SER
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SNP: rs121918455,
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ClinVar: RCV000014255, RCV000033518, RCV000037669, RCV000157682, RCV000515421, RCV000588570, RCV001027696, RCV001197417, RCV001813193, RCV004532339
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<p>In affected members of 2 families with Noonan syndrome (NS1; 163950), Tartaglia et al. (2002) identified an 923A-G transition in the PTPN11 gene, resulting in an asn308-to-ser (N308S) substitution. This mutation occurs in the same codon as the common N308D mutation (176876.0003); thus, codon 308 is a hotspot for Noonan syndrome. One of the 2 families in which the N308S mutation was observed had typical features of Noonan syndrome associated with multiple giant cell lesions in bone. </p><p>In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. </p>
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<span class="mim-font">
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<strong>.0005 LEOPARD SYNDROME 1</strong>
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PTPN11, TYR279CYS
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SNP: rs121918456,
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ClinVar: RCV000030620, RCV000033504, RCV000055890, RCV000077859, RCV000492270, RCV000577894, RCV000617951, RCV000768062, RCV000824744, RCV001000775, RCV001813194, RCV004528108
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<p>In 3 patients with LEOPARD syndrome-1 (LPRD1; 151100), Digilio et al. (2002) found an A-to-G transition at nucleotide 836 in exon 7 of the PTPN11 gene resulting in a tyr279-to-cys (Y279C) mutation. </p><p>Yoshida et al. (2004) identified heterozygosity for the Y279C mutation in 2 Japanese patients with LEOPARD syndrome. </p><p>In a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, Alfurayh et al. (2020) identified the Y279C mutation. The mutation was identified by next-generation sequencing. All 3 patients had normal stature. The father had hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect. </p><p>Edouard et al. (2010) found that the Y279C mutation caused elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; 171833). PI3 kinase hyperactivation in Y279C mutant cells also enhanced myocardin (MYOCD; 606127)/SRF (600589) activity. </p>
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<span class="mim-font">
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<strong>.0006 LEOPARD SYNDROME 1</strong>
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PTPN11, THR468MET
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SNP: rs121918457,
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gnomAD: rs121918457,
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ClinVar: RCV000033533, RCV000055884, RCV000077851, RCV000106323, RCV000157014, RCV000208002, RCV000515406, RCV000723326, RCV000853462, RCV001813197, RCV002390104
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<p>In 5 unrelated patients and in a mother-daughter pair with LEOPARD syndrome-1 (LPRD1; 151100), Digilio et al. (2002) found a thr468-to-met (T468M) mutation resulting from a C-to-T transition at nucleotide 1403 in exon 12 of the PTPN11 gene. </p><p>Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in the PTPN11 gene. The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of NFATC4 (602699) in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlated with a potential hypertrophic state. Carvajal-Vergara et al. (2010) also provided molecular insights into signaling pathways that may promote the disease phenotype. Carvajal-Vergara et al. (2010) showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines. </p><p>Edouard et al. (2010) found that the T468M mutation caused elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; 171833). PI3 kinase hyperactivation in T468M mutant cells also enhanced myocardin (MYOCD; 606127)/SRF (600589) activity and promoted hypertrophic growth in cultured chicken embryo myocardial cushions and primary human cardiomyocytes. </p><p>In a Chinese boy (patient 3) with cafe-au-lait spots and freckles over the face and trunk, who also had dysmorphic facial features including hypertelorism, and pectus excavatum, Zhang et al. (2016) identified heterozygosity for the PTPN11 T468M mutation, which was not found in unaffected family members or in 100 controls. </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>.0007 NOONAN SYNDROME 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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PTPN11, SER502THR
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<br />
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SNP: rs121918458,
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ClinVar: RCV000014260, RCV000033543, RCV000156995, RCV000212897, RCV001851849, RCV002490364, RCV004532342, RCV004984639
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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>Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T) substitution in exon 13 in 2 unrelated subjects with Noonan syndrome (NS1; 163950). </p><p>Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a Japanese infant with Noonan syndrome and the S502T mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 NOONAN SYNDROME 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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PTPN11, TYR63CYS
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<br />
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SNP: rs121918459,
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gnomAD: rs121918459,
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ClinVar: RCV000014261, RCV000033468, RCV000077857, RCV000157000, RCV000515408, RCV000588678, RCV000722014, RCV001249667, RCV001813198, RCV003137518, RCV003147286, RCV004528109
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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 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This same mutation was identified by Tartaglia et al. (2001). This mutation was also identified by Kosaki et al. (2002) in 2 patients. </p><p>See 176876.0004 and Becker et al. (2007). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 NOONAN SYNDROME 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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PTPN11, TYR62ASP
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<br />
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SNP: rs121918460,
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gnomAD: rs121918460,
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ClinVar: RCV000014257, RCV000033466, RCV000153794, RCV000156993, RCV000590972, RCV000762882, RCV000824739, RCV001813195, RCV002408460, RCV004532340
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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 subject with Noonan syndrome (NS1; 163950), Maheshwari et al. (2002) found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene. This same mutation was identified by Tartaglia et al. (2002). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 NOONAN SYNDROME 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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PTPN11, ASP61GLY
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<br />
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SNP: rs121918461,
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ClinVar: RCV000014258, RCV000033464, RCV000077856, RCV000156984, RCV000626829, RCV000824738, RCV001270166, RCV001376030, RCV001813196, RCV002490363, RCV003147285, RCV004532341
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) found an A-to-G transition at nucleotide 182 in exon 3 of the PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid substitution. </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>.0011 NOONAN SYNDROME 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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PTPN11, THR73ILE
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<br />
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SNP: rs121918462,
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ClinVar: RCV000014262, RCV000033475, RCV000156985, RCV000212891, RCV000515312, RCV001813199, RCV002415414, RCV003147287, RCV003147288
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) identified a 218C-T transition in exon 3 of the PTPN11 gene, resulting in a thr73-to-ile (T73I) substitution. </p><p>In 4 children with Noonan syndrome who developed juvenile myelomonocytic leukemia, Tartaglia et al. (2003) observed a heterozygous germline T73I mutation, which alters the N-terminal Src homology 2 (SH2) domain. The T73I mutation was also identified in an individual with growth retardation, pulmonic stenosis, and JMML. Analysis of germline and parental DNAs indicated that the mutations were de novo germline events. </p><p>Jongmans et al. (2005) described a patient with Noonan syndrome and mild JMML who carried the T73I mutation. </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>.0012 NOONAN SYNDROME 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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|
|
PTPN11, PHE285SER
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<br />
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|
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SNP: rs121918463,
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|
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|
|
ClinVar: RCV000014263, RCV000037663, RCV000077862, RCV000190417, RCV000458650, RCV001376066, RCV001813200, RCV004532343, RCV004562207, RCV004562208
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|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) found a T-to-C transition at nucleotide 854 in exon 8 of the PTPN11 gene, resulting in a phe285-to-ser (F285S) amino acid substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0013 MOVED TO 176876.0011</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLU76LYS
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|
|
<br />
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|
|
SNP: rs121918464,
|
|
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|
|
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|
|
ClinVar: RCV000014264, RCV000033476, RCV000156974, RCV000212892, RCV001254876, RCV004545728, RCV004813039
|
|
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|
|
|
</span>
|
|
</div>
|
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<div>
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|
<span class="mim-text-font">
|
|
<p>Tartaglia et al. (2003) identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML (607785) but without Noonan syndrome. A 226G-A transition predicting a glu76-to-lys (E76K) substitution within the N-SH2 domain accounted for 25% of the total number of mutations. Codon 76 was a mutation hotspot for JMML, with 4 different amino acid substitutions predicted among 8 individuals: in addition to E76K, which was present in 5 cases, E76V (176876.0015), E76G (176876.0016), and E76A (176876.0017) were each present in 1 case. </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>.0015 LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLU76VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918465,
|
|
|
|
|
|
|
|
ClinVar: RCV000014265, RCV000781775, RCV000788241, RCV001813201
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 176876.0014 and Tartaglia et al. (2003). </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLU76GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918465,
|
|
|
|
|
|
|
|
ClinVar: RCV000014266, RCV000159046, RCV002513040
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 176876.0014 and Tartaglia et al. (2003). </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>.0017 LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC</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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PTPN11, GLU76ALA
|
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<br />
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|
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SNP: rs121918465,
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|
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ClinVar: RCV000014267, RCV000033477
|
|
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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>See 176876.0014 and Tartaglia et al. (2003). </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>.0018 NOONAN SYNDROME</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">
|
|
|
|
PTPN11, GLN79ARG
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<br />
|
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|
|
SNP: rs121918466,
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|
|
ClinVar: RCV000014268, RCV000033480, RCV000037641, RCV000157680, RCV000515381, RCV000590740, RCV001813202, RCV002453257, RCV004532344
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 10 affected members from a large 4-generation Belgian family with Noonan syndrome (NS1; 163950) and some features suggestive of cardiofaciocutaneous syndrome (115150), Schollen et al. (2003) identified a 236A-G transition in exon 3 of the PTPN11 gene, resulting in a gln79-to-arg (Q79R) mutation. The mutation was not found in 7 unaffected relatives or 3 spouses. </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>.0019 NOONAN SYNDROME</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
PTPN11, THR411MET
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<br />
|
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|
|
SNP: rs121918467,
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|
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|
|
gnomAD: rs121918467,
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|
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ClinVar: RCV000014269, RCV001030087, RCV001091427, RCV001293768, RCV002362582
|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old female with clinical features of Noonan syndrome (NS1; 163950) but with some characteristics of cardiofaciocutaneous syndrome (CFC; 115150) as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation, Bertola et al. (2004) identified a T-to-C transition in exon 11 of the PTPN11 gene, resulting in a thr411-to-met (T411M) substitution. Molecular dynamic studies indicated that this mutation favors a more active protein conformation. The mutation was also found in the patient's mother and older sister, who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 LEOPARD SYNDROME 1</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
PTPN11, ALA461THR
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|
<br />
|
|
|
|
SNP: rs121918468,
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|
|
|
|
ClinVar: RCV000033530, RCV000037611, RCV000055882, RCV000529342, RCV001002017, RCV001089941, RCV004532345
|
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|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a Japanese patient with LEOPARD syndrome (LPRD1; 151100), Yoshida et al. (2004) identified heterozygosity for a 1381G-A transition in exon 12 of the PTPN11 gene, resulting in an ala461-to-thr (A461T) substitution. </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>.0021 LEOPARD SYNDROME 1</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
PTPN11, GLY464ALA
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|
<br />
|
|
|
|
SNP: rs121918469,
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|
|
ClinVar: RCV000033531, RCV000055883, RCV000077850, RCV000824746, RCV001281363, RCV001813203, RCV002390105, RCV004532346
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with LEOPARD syndrome (LPRD1; 151100), Yoshida et al. (2004) identified heterozygosity for a 1391G-C transversion in exon 12 of the PTPN11 gene, resulting in a gly464-to-ala (G464A) substitution. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 LEOPARD SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLN510PRO
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<br />
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|
|
SNP: rs121918470,
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|
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|
|
|
gnomAD: rs121918470,
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|
|
ClinVar: RCV000014272, RCV000033554, RCV000210036, RCV000520822, RCV000586289, RCV000824752, RCV001254107, RCV002286696, RCV004541003
|
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|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the proband of a family with 3 individuals with LEOPARD syndrome (LPRD1; 151100), Kalidas et al. (2005) found a 1529A-C transversion in exon 13 of the PTPN11 gene resulting in a gln510-to-pro (Q510P) substitution. </p><p>Edouard et al. (2010) found that PTPN11 with the Q510P mutation elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in transfected HEK293 cells compared with wildtype PTPN11. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (PIK3R1; 171833). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLN510ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918470,
|
|
|
|
|
|
gnomAD: rs121918470,
|
|
|
|
|
|
ClinVar: RCV000014273, RCV000414743, RCV000780654, RCV001002770, RCV004018624, RCV004734518
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bertola et al. (2005) described a girl with both neurofibromatosis I (162200) and Noonan syndrome (NS1; 163950) who had a de novo mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene inherited from her father who was mildly affected with Noonan syndrome. The PTPN11 mutation was a 1909A-G transition, resulting in a gln510-to-arg substitution. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 3-BP DEL, 181GTG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918471, rs80338836,
|
|
|
|
|
|
|
|
ClinVar: RCV000014274, RCV002513041
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with Noonan syndrome (NS1; 163950), Yoshida et al. (2004) identified a 3-bp deletion in exon 3 of the PTPN11 gene, 181delGTG, that resulted in deletion of the gly60 codon in the N-SH2 domain of the protein. Because gly60 is directly involved in the N-SH2/PTP interaction, loss of this residue was predicted to disrupt N-SH2/PTP binding, activating the phosphatase function. Yoshida et al. (2004) stated that 181delGTG was the sole deletion mutation identified in the PTPN11 gene to that time. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 11-BP DEL, NT514
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000014275
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 5-generation family segregating autosomal dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified heterozygosity for an 11-bp deletion (514del11) in exon 4 of the PTPN11 gene, predicted to cause a frameshift leading to a new sequence of 12 codons followed by a premature stop codon. Two apparently unaffected individuals who carried the deletion were found upon examination to have manifestations of the disease. The mutation was not found in 469 controls, 60% of whom were ethnically matched. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, ARG138TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606989,
|
|
|
|
|
|
gnomAD: rs267606989,
|
|
|
|
|
|
ClinVar: RCV000014276, RCV001205820
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation family segregating autosomal dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified heterozygosity for a C-to-T transition in exon 4 of the PTPN11 gene, resulting in an arg138-to-ter (R138X) substitution. A brother and sister, both parents of affected children, were unaffected carriers of the mutation, indicating incomplete penetrance. The mutation was not found in 469 controls, 60% of whom were ethnically matched. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, THR2ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606990,
|
|
|
|
|
|
|
|
ClinVar: RCV000014277, RCV000033445, RCV000211847, RCV000694389, RCV000988912, RCV002496356, RCV003156060, RCV004795408
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with both Noonan syndrome (NS1; 163950) and neurofibromatosis I (162200), Thiel et al. (2009) found compound heterozygosity for 2 mutations: a de novo 5C-T transition in the PTPN11 gene, resulting in a thr2-to-ile (T2I) substitution, and a splice site mutation in the NF1 gene (613113.0044). The PTPN11 mutation was predicted to destabilize the inactive form of PTPN11, resulting in increased basal activity and a gain of function. The proband had hypertelorism, low-set ears, short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. The NF1 mutation was inherited from her mother who had mild features of neurofibromatosis I. The proband's brother, who carried the heterozygous NF1 mutation, also had mild features of neurofibromatosis I. Neither the mother nor the brother had optic gliomas. However, the girl developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were also reported by Bertola et al. (2005) in a patient with a combination of neurofibromatosis I and Noonan syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 5-BP DEL, NT409
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122857,
|
|
|
|
|
|
|
|
ClinVar: RCV000024255
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family (family A) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 5-bp deletion in exon 4 of the PTPN11 gene (409_413del5) resulting in a frameshift (Val137ArgfsTer17). The mutation was not found in an unaffected family member. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 11-BP DEL/24-BP INS, NT458
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122858,
|
|
|
|
|
|
|
|
ClinVar: RCV000024256
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family (family B) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous complex deletion/insertion mutation in exon 4 of the PTPN11 gene (458_468del11ins24), resulting in a frameshift (Thr153LysfsTer8). The mutation was not found in an unaffected family member. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 2-BP DEL, NT353
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122859,
|
|
|
|
|
|
|
|
ClinVar: RCV000024257
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family (family C) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 2-bp deletion in exon 4 of the PTPN11 gene (353_354del2), resulting in a frameshift (Ser118TrpfsTer10). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, GLN506TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907157,
|
|
|
|
|
|
|
|
ClinVar: RCV000024258
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family (family E) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 1516C-T transition in exon 13 of the PTPN11 gene, resulting in a gln506-to-ter (Q506X) nonsense mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, 1-BP DEL, NT1315
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122860,
|
|
|
|
|
|
|
|
ClinVar: RCV000024259
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family (family D) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 1-bp deletion in exon 11 of the PTPN11 gene (1315del1), resulting in a frameshift (Leu439TrpfsTer33). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 METACHONDROMATOSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTPN11, IVS5AS, A-C, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122861,
|
|
|
|
|
|
|
|
ClinVar: RCV000024260
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected sibs in a family (family F) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous acceptor splice site mutation in intron 5 of the PTPN11 gene (643-2A-C). The mutation was not found in either parent, including the affected mother. Bowen et al. (2011) suggested that the mother was mosaic for a PTPN11 mutation. </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>
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<span class="mim-font">
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<strong>.0034 METACHONDROMATOSIS</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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PTPN11, LYS99TER
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<br />
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SNP: rs387907158,
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ClinVar: RCV000024261
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family (family I) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 295A-T transversion in exon 3 of the PTPN11 gene, resulting in a lys99-to-ter (K99X) nonsense mutation. </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>.0035 METACHONDROMATOSIS</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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PTPN11, IVS9AS, G-T, -1
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<br />
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SNP: rs398122862,
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ClinVar: RCV000024262
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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 an affected member of a family (family G) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous acceptor splice site mutation in intron 9 of the PTPN11 gene (1093-1G-T). </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>.0036 METACHONDROMATOSIS</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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PTPN11, 15-KB DEL
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<br />
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ClinVar: RCV000024263
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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>Using copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene, Bowen et al. (2011) identified heterozygosity for a 15-kb deletion spanning exon 7 of the PTPN11 gene (Thr253LeufsTer54) in a patient (patient S) with metachondromatosis (METCDS; 156250). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<strong>A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains.</strong>
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[PubMed: 7681589]
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<p class="mim-text-font">
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Alfurayh, N., Alsaif, F., Alballa, N., Zeitouni, L., Ramzan, K., Imtiaz, F., Alakeel, A.
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<strong>LEOPARD syndrome with PTPN11 gene mutation in three family members presenting with different phenotypes.</strong>
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Bastien, L., Ramachandran, C., Liu, S., Adam, M.
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<strong>Cloning, expression, and mutational analysis of SH-PTP2, human protein-tyrosine phosphatase 2-domains.</strong>
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Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M.
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<strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong>
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Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., Maris, J. M., Richardson, A., Bardelli, A., Sugarbaker, D. J., Richards, W. G., Du, J., and 9 others.
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<strong>Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia.</strong>
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<p class="mim-text-font">
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Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E.
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<strong>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.</strong>
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[PubMed: 15384080]
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<p class="mim-text-font">
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Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E.
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<strong>Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong>
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[Full Text: https://doi.org/10.1002/ajmg.a.30813]
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<p class="mim-text-font">
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Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., and 16 others.
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<strong>Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.</strong>
|
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PLoS Genet. 7: e1002050, 2011. Note: Electronic Article.
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[PubMed: 21533187]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002050]
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<p class="mim-text-font">
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Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others.
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<strong>Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.</strong>
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Nature 465: 808-812, 2010.
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[PubMed: 20535210]
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[Full Text: https://doi.org/10.1038/nature09005]
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<p class="mim-text-font">
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Chen, B., Bronson, R. T., Klaman, L. D., Hampton, T. G., Wang, J., Green, P. J., Magnuson, T., Douglas, P. S., Morgan, J. P., Neel, B. G.
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<strong>Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis.</strong>
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Nature Genet. 24: 296-299, 2000.
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[PubMed: 10700187]
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<p class="mim-text-font">
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Chen, Y.-N. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcia-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H.-T., Chen, Z., Cooke, V. G., Dobson, J. R., Deng, Z., and 41 others.
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<strong>Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.</strong>
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Nature 535: 148-152, 2016.
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[PubMed: 27362227]
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[Full Text: https://doi.org/10.1038/nature18621]
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<p class="mim-text-font">
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Coulombe, G., Leblanc, C., Cagnol, S., Maloum, F., Lemieux, E., Perrault, N., Feng, G.-S., Boudreau, F., Rivard, N.
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<strong>Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice.</strong>
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Molec. Cell. Biol. 33: 2275-2284, 2013.
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[PubMed: 23530062]
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<p class="mim-text-font">
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Dechert, U., Duncan, A. M. V., Bastien, L., Duff, C., Adam, M., Jirik, F. R.
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<strong>Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is localized to 12q24.1-24.3.</strong>
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Digilio, M. C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B.
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<strong>Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.</strong>
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Am. J. Hum. Genet. 71: 389-394, 2002.
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<p class="mim-text-font">
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Dong, L., Yu, W.-M., Zheng, H., Loh, M. L., Bunting, S. T., Pauly, M., Huang, G., Zhou, M., Broxmeyer, H. E., Scadden, D. T., Qu, C.-K.
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<strong>Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment.</strong>
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<p class="mim-text-font">
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Edouard, T., Combier, J.-P., Nedelec, A., Bel-Vialar, S., Metrich, M., Conte-Auriol, F., Lyonnet, S., Parfait, B., Tauber, M., Salles, J.-P., Lezoualc'h, F., Yart, A., Raynal, P.
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<strong>Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3-beta signaling.</strong>
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<li>
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<p class="mim-text-font">
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Gauthier, A. S., Furstoss, O., Araki, T., Chan, R., Neel, B. G., Kaplan, D. R., Miller, F. D.
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<strong>Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome.</strong>
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Neuron 54: 245-262, 2007.
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[PubMed: 17442246]
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[Full Text: https://doi.org/10.1016/j.neuron.2007.03.027]
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</p>
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<li>
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<p class="mim-text-font">
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Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M.
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<strong>Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.</strong>
|
|
Am. J. Med. Genet. 149A: 2122-2128, 2009.
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[PubMed: 19760651]
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[Full Text: https://doi.org/10.1002/ajmg.a.32992]
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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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He, Z., Zhang, S. S., Meng, Q., Li, S., Zhu, H. H., Raquil, M.-A., Alderson, N., Zhang, H., Wu, J., Rui, L., Cai, D., Feng, G.-S.
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<strong>Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals.</strong>
|
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Molec. Cell. Biol. 32: 1867-1878, 2012.
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[PubMed: 22431513]
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[Full Text: https://doi.org/10.1128/MCB.06712-11]
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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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|
Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T, Asaka, M., Hatakeyama, M.
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<strong>SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.</strong>
|
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Science 295: 683-686, 2002.
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[PubMed: 11743164]
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[Full Text: https://doi.org/10.1126/science.1067147]
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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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Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J., Shoelson, S. E.
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<strong>Crystal structure of the tyrosine phosphatase SHP-2.</strong>
|
|
Cell 92: 441-450, 1998.
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[PubMed: 9491886]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80938-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Ion, A., Tartaglia, M., Song, X., Kalidas, K., van der Burgt, I., Shaw, A. C., Ming, J. E., Zampino, G., Zackai, E. H., Dean, J. C. S., Somer, M., Parenti, G., Crosby, A. H., Patton, M. A., Gelb, B. D., Jeffery, S.
|
|
<strong>Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.</strong>
|
|
Hum. Genet. 111: 421-427, 2002.
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|
|
[PubMed: 12384786]
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[Full Text: https://doi.org/10.1007/s00439-002-0803-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Isobe, M., Hinoda, Y., Imai, K., Adachi, M.
|
|
<strong>Chromosomal localization of an SH2 containing tyrosine phosphatase (SH-PTP3) gene to chromosome 12q24.1.</strong>
|
|
Oncogene 9: 1751-1753, 1994.
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[PubMed: 8183573]
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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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Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I.
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|
<strong>Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature.</strong>
|
|
Am. J. Med. Genet. 134A: 165-170, 2005.
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|
[PubMed: 15723289]
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[Full Text: https://doi.org/10.1002/ajmg.a.30598]
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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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