6955 lines
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Entry
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- *607379 - NF2, MOESIN-EZRIN-RADIXIN-LIKE (MERLIN) TUMOR SUPPRESSOR; NF2
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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">*607379</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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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<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/607379">Table View</a>
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</li>
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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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</nav>
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</div>
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</div>
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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=ENSG00000186575;t=ENST00000338641" 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=4771" 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=607379" 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=ENSG00000186575;t=ENST00000338641" 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_000268,NM_001407053,NM_001407054,NM_001407055,NM_001407056,NM_001407057,NM_001407058,NM_001407059,NM_001407060,NM_001407062,NM_001407063,NM_001407064,NM_001407065,NM_001407066,NM_001407067,NM_016418,NM_181825,NM_181828,NM_181829,NM_181830,NM_181831,NM_181832,NM_181833,NR_176267,XM_017028809,XM_047441386" 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_000268" 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=607379" 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=06980&isoform_id=06980_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/NF2" 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/292292,312043,462594,463121,688373,688375,688377,825719,3980300,3980301,4261839,4557795,5730864,5730866,5730868,6855625,8895103,14133884,14133887,14133893,14133896,14133899,14133902,14133905,14133970,14133973,18044276,32451486,32967254,32967260,32967262,32967264,32967266,32967268,32967514,37514853,47678591,119580218,119580219,119580220,119580221,119580222,119580223,119580224,119580225,119580226,119580227,119580228,119580229,119580230,119580231,119580232,119580233,119580234,119580235,119580236,119580237,145558663,221041650,1034629014,1241066601,1241066603,1241066605,2217339761,2243791004,2244985390,2244985392,2244985456,2244985464,2244985468,2244985488,2244985542,2244985600,2244985634,2244986445,2244986488,2244986494,2244986630,2462584934,2462584936" 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/P35240" 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=4771" 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=ENSG00000186575;t=ENST00000338641" 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=NF2" 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=NF2" 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+4771" 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/NF2" 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:4771" 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/4771" 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=chr22&hgg_gene=ENST00000338641.10&hgg_start=29603556&hgg_end=29698600&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:7773" 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:7773" 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://medlineplus.gov/genetics/gene/nf2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607379[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=607379[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/NF2/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/ENSG00000186575" 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=NF2" 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=NF2" 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=NF2" 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=NF2&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/PA31580" 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:7773" 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/FBgn0086384.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:97307" 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/NF2#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:97307" 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/4771/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=4771" 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=WBGene00003593;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-040622-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607379" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4771" 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=NF2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607379
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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NF2, MOESIN-EZRIN-RADIXIN-LIKE (MERLIN) TUMOR SUPPRESSOR; NF2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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NEUROFIBROMIN 2<br />
|
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MERLIN<br />
|
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SCHWANNOMIN; SCH
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NF2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NF2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/22/155?start=-3&limit=10&highlight=155">22q12.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:29603556-29698600&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'})">22:29,603,556-29,698,600</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607174,101000,101000" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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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>Cell-cell contact between normal cultured diploid cells results in inhibition of proliferation despite the unlimited availability of nutrients and growth-promoting factors. A similar phenomenon occurs in vivo in all adult solid tissues. NF2 is a critical regulator of contact-dependent inhibition of proliferation and functions at the interface between cell-cell adhesion, transmembrane signaling, and the actin cytoskeleton (<a href="#14" class="mim-tip-reference" title="Curto, M., McClatchey, A. <strong>Nf2/Merlin: a coordinator of receptor signalling and intercellular contact.</strong> Brit. J. Cancer 98: 256-262, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17971776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17971776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17971776[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.6604002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17971776">Curto and McClatchey, 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17971776" 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="#63" class="mim-tip-reference" title="Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munroe, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., Gusella, J. F. <strong>A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.</strong> Cell 72: 791-800, 1993. Note: Erratum: Cell 75: 826 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8453669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8453669</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90406-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8453669">Trofatter et al. (1993)</a> identified a candidate gene responsible for neurofibromatosis-2 (NF2), now known as vestibular schwannomatosis or NF2-related schwannomatosis (SWNV; <a href="/entry/101000">101000</a>). The authors suggested that it was a tumor suppressor gene and observed nonoverlapping deletions in DNA from 2 independent NF2 families as well as alterations in the meningiomas from 2 unrelated NF2 patients. The candidate gene encodes a deduced 595-amino acid protein with striking similarity to several members of the ERM family of proteins proposed to link cytoskeletal components with proteins in the cell membrane; these include ezrin (<a href="/entry/123900">123900</a>), radixin (<a href="/entry/179410">179410</a>), and moesin (<a href="/entry/309845">309845</a>). Because of the resemblance to these 3 proteins (45-47% identity), <a href="#63" class="mim-tip-reference" title="Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munroe, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., Gusella, J. F. <strong>A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.</strong> Cell 72: 791-800, 1993. Note: Erratum: Cell 75: 826 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8453669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8453669</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90406-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8453669">Trofatter et al. (1993)</a> called the NF2 gene product merlin. The authors suggested that the NF2 gene may represent a novel class of tumor suppressor genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8453669" 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="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> likewise isolated a gene, which they designated schwannomin (SCH), bearing homology to erythrocyte protein 4.1 and the ezrin/moesin/talin family of genes. To isolate the gene, they cloned the region between 2 flanking polymorphic markers in which they found several genes. One of the identified genes was the site of germline mutations in patients with neurofibromatosis-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8379998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By assembling overlapping cDNA fragments, <a href="#12" class="mim-tip-reference" title="Chang, L.-S., Akhmametyeva, E. M., Wu, Y., Zhu, L., Welling, D. B. <strong>Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts.</strong> Genomics 79: 63-76, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11827459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11827459</a>] [<a href="https://doi.org/10.1006/geno.2001.6672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11827459">Chang et al. (2002)</a> obtained a complete NF2 cDNA. Northern blot analysis revealed a major 6.1-kb transcript expressed ubiquitously and a minor 2.7-kb transcript expressed in multiple tissues and several human cell lines. Some tissues also expressed a 3.9-kb transcript. The ratio of expression of the 6.1- and 2.7-kb transcripts was tissue specific. <a href="#12" class="mim-tip-reference" title="Chang, L.-S., Akhmametyeva, E. M., Wu, Y., Zhu, L., Welling, D. B. <strong>Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts.</strong> Genomics 79: 63-76, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11827459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11827459</a>] [<a href="https://doi.org/10.1006/geno.2001.6672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11827459">Chang et al. (2002)</a> found that NF2 transcription initiates at several possible start sites and that there are 8 alternatively spliced isoforms. The predominant isoforms were designated II and I (full length and lacking exon 16, respectively). The next most frequent isoforms had deletions of exon 2, exon 3, or both. All other isoforms were expressed at low frequency. <a href="#12" class="mim-tip-reference" title="Chang, L.-S., Akhmametyeva, E. M., Wu, Y., Zhu, L., Welling, D. B. <strong>Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts.</strong> Genomics 79: 63-76, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11827459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11827459</a>] [<a href="https://doi.org/10.1006/geno.2001.6672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11827459">Chang et al. (2002)</a> concluded that use of multiple polyadenylation sites likely contributes to the complexity of NF2 transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11827459" 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="Chang, L.-S., Akhmametyeva, E. M., Wu, Y., Zhu, L., Welling, D. B. <strong>Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts.</strong> Genomics 79: 63-76, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11827459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11827459</a>] [<a href="https://doi.org/10.1006/geno.2001.6672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11827459">Chang et al. (2002)</a> analyzed the promoter region of NF2. They identified a GC-rich region, but no consensus TATA sequence. Using an NF2 promoter-luciferase chimeric plasmid transfected into several cell lines, they identified a positive cis-acting element within the GC-rich sequence that could bind SP1 (<a href="/entry/189906">189906</a>) and GCF (<a href="/entry/189901">189901</a>), and they identified a negative regulatory element. By cotransfection in Drosophila cells, they confirmed that SP1 could activate the NF2 promoter through the GC-rich sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11827459" 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="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> and <a href="#63" class="mim-tip-reference" title="Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munroe, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., Gusella, J. F. <strong>A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.</strong> Cell 72: 791-800, 1993. Note: Erratum: Cell 75: 826 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8453669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8453669</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90406-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8453669">Trofatter et al. (1993)</a> determined that the NF2 gene contains 17 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8453669+8379998" 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>The combined use of family linkage studies and tumor deletion mapping by <a href="#66" class="mim-tip-reference" title="Wertelecki, W., Rouleau, G. A., Superneau, D. W., Forehand, L. W., Williams, J. P., Haines, J. L., Gusella, J. F. <strong>Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred.</strong> New Eng. J. Med. 319: 278-283, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3134615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3134615</a>] [<a href="https://doi.org/10.1056/NEJM198808043190505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3134615">Wertelecki et al. (1988)</a>, <a href="#48" class="mim-tip-reference" title="Rouleau, G. A., Seizinger, B. R., Wertelecki, W., Haines, J. L., Superneau, D. W., Martuza, R. L., Gusella, J. F. <strong>Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22.</strong> Am. J. Hum. Genet. 46: 323-328, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2105641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2105641</a>]" pmid="2105641">Rouleau et al. (1990)</a>, <a href="#67" class="mim-tip-reference" title="Wolff, R. K., Frazer, K. A., Jackler, R. K., Lanser, M. J., Pitts, L. H., Cox, D. R. <strong>Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors.</strong> Am. J. Hum. Genet. 51: 478-485, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1496981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1496981</a>]" pmid="1496981">Wolff et al. (1992)</a>, and <a href="#2" class="mim-tip-reference" title="Arai, E., Ikeuchi, T., Karasawa, S., Tamura, A., Yamamoto, K., Kida, M., Ichimura, K., Yuasa, Y., Tonomura, A. <strong>Constitutional translocation t(4;22)(q12;q12.2) associated with neurofibromatosis type 2.</strong> Am. J. Med. Genet. 44: 163-167, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1456285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1456285</a>] [<a href="https://doi.org/10.1002/ajmg.1320440209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1456285">Arai et al. (1992)</a> localized the NF2 gene to chromosome 22q12.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2105641+3134615+1456285+1496981" 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="#13" class="mim-tip-reference" title="Claudio, J. O., Malo, D., Rouleau, G. A. <strong>The mouse neurofibromatosis type 2 gene maps to chromosome 11.</strong> Genomics 21: 437-439, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088840</a>] [<a href="https://doi.org/10.1006/geno.1994.1291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088840">Claudio et al. (1994)</a> demonstrated that the mouse homolog of the NF2 gene is located in the proximal region of chromosome 11. The localization was achieved by analysis of allele distribution in recombinant inbred strains using a simple sequence repeat polymorphism in the 3-prime untranslated region of the mouse NF2 cDNA. The region of chromosome 11 also contains genes for leukemia inhibitory factor (LIF; <a href="/entry/159540">159540</a>) and neurofilament heavy chain polypeptide (NFH; <a href="/entry/162230">162230</a>), both of which map to the same region of human chromosome 22 as does NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Gutmann, D. H., Sherman, L., Seftor, L., Haipek, C., Lu, K. H., Hendrix, M. <strong>Increased expression of the NF2 tumor suppressor gene product, merlin, impairs cell motility, adhesion and spreading.</strong> Hum. Molec. Genet. 8: 267-275, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931334</a>] [<a href="https://doi.org/10.1093/hmg/8.2.267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931334">Gutmann et al. (1999)</a> studied rat schwannoma cell lines overexpressing wildtype merlin isoforms and mutant merlin proteins. Overexpression of wildtype merlin resulted in transient alterations in F-actin organization, cell spreading, and cell attachment, and in impaired cell motility as measured in an in vitro motility assay. These effects were observed only in cells overexpressing a merlin isoform capable of inhibiting cell growth and not with mutant merlin molecules (harboring NF2 patient mutations) or a merlin splice variant (isoform II) lacking growth-inhibitory activity. These data indicated that merlin may function to maintain normal cytoskeletal organization, and suggested that its influence on cell growth depends on specific cytoskeletal rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931334" 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 yeast 2-hybrid and pull-down analyses, <a href="#22" class="mim-tip-reference" title="Goutebroze, L., Brault, E., Muchardt, C., Camonis, J., Thomas, G. <strong>Cloning and characterization of SCHIP-1, a novel protein interacting specifically with spliced isoforms and naturally occurring mutant NF2 proteins.</strong> Molec. Cell. Biol. 20: 1699-1712, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10669747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10669747</a>] [<a href="https://doi.org/10.1128/MCB.20.5.1699-1712.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10669747">Goutebroze et al. (2000)</a> showed that SCHIP1 (<a href="/entry/619206">619206</a>) interacted with schwannomin. Mutation analysis revealed that the predicted coiled-coil region of SCHIP1 was required for efficient interaction with schwannomin. Immunoprecipitation assays showed that, in vivo, SCHIP1 interacted only with some naturally occurring schwannomin mutants, or a schwannomin isoform produced from a variant lacking exons 2 and 3, but not with a schwannomin isoform exhibiting growth-suppressive activity. The authors concluded that the SCHIP1-schwannomin interaction is regulated by conformational changes in schwannomin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10669747" 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="Gutmann, D. H., Hirbe, A. C., Haipek, C. A. <strong>Functional analysis of neurofibromatosis 2 (NF2) missense mutations.</strong> Hum. Molec. Genet. 10: 1519-1529, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11448944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11448944</a>] [<a href="https://doi.org/10.1093/hmg/10.14.1519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11448944">Gutmann et al. (2001)</a> performed a detailed functional analysis of 8 naturally occurring nonconservative missense mutations in the NF2 gene. The authors analyzed proliferation, actin cytoskeleton-mediated events, and merlin folding in a regulatable expression system in rat schwannoma cells. They demonstrated that mutations clustered in the predicted alpha-helical region did not impair the function of merlin, whereas those in either the N- or C-terminus of the protein rendered merlin inactive as a negative growth regulator. The authors suggested that the key functional domains of merlin may lie within the highly conserved FERM domain and the unique C terminus of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11448944" 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="#23" class="mim-tip-reference" title="Gutmann, D. H., Haipek, C. A., Burke, S. P., Sun, C.-X., Scoles, D. R., Pulst, S. M. <strong>The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the 'open' conformation and suppresses cell growth and motility.</strong> Hum. Molec. Genet. 10: 825-834, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11285248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11285248</a>] [<a href="https://doi.org/10.1093/hmg/10.8.825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11285248">Gutmann et al. (2001)</a> stated that the merlin protein functions as a negative growth regulator. They demonstrated that regulated overexpression of the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS, or HRS; <a href="/entry/604375">604375</a>) in rat schwannoma cells yielded effects similar to those seen with overexpression of merlin, including growth inhibition, decreased motility, and abnormalities in cell spreading. The HRS binding domain of merlin was mapped to residues 453-557. Overexpression of C-terminal merlin had no effect on HRS function, suggesting to the authors that merlin binding to HRS does not negatively regulate HRS growth suppressor activity, and that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways. <a href="#26" class="mim-tip-reference" title="Gutmann, D. H. <strong>The neurofibromatoses: when less is more.</strong> Hum. Molec. Genet. 10: 747-755, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257108</a>] [<a href="https://doi.org/10.1093/hmg/10.7.747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257108">Gutmann (2001)</a> reviewed the functions of neurofibromin (<a href="/entry/613113">613113</a>) and merlin in tumor suppression and cell-cell signaling, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11257108+11285248" 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 yeast 2-hybrid interaction cloning, <a href="#55" class="mim-tip-reference" title="Scoles, D. R., Huynh, D. P., Chen, M. S., Burke, S. P., Gutmann, D. H., Pulst, S.-M. <strong>The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate.</strong> Hum. Molec. Genet. 9: 1567-1574, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861283</a>] [<a href="https://doi.org/10.1093/hmg/9.11.1567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861283">Scoles et al. (2000)</a> determined that schwannomin interacts with HRS. They demonstrated the interaction both in vivo, by immunoprecipitation of endogenous HRS with endogenous schwannomin, and in vitro, with a binding assay using bacterially purified HRS and schwannomin. The regions of interaction included schwannomin residues 256-579 and HRS residues from 480 to the end of either of 2 HRS isoforms. Schwannomin molecules with an L46R, L360P, L535P, or Q538P missense mutation demonstrated reduced affinity for HRS binding. Since HRS is associated with early endosomes and may mediate receptor translocation to the lysosome, the authors used indirect immunofluorescence to demonstrate that schwannomin and HRS colocalize at endosomes in STS26T Schwann cells. The authors hypothesized that schwannomin is involved in HRS-mediated cell signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861283" 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="#62" class="mim-tip-reference" title="Sun, C.-X., Haipek, C., Scoles, D. R., Pulst, S. M., Giovannini, M., Komada, M., Gutmann, D. H. <strong>Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate.</strong> Hum. Molec. Genet. 11: 3167-3178, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444101</a>] [<a href="https://doi.org/10.1093/hmg/11.25.3167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12444101">Sun et al. (2002)</a> generated a series of HRS truncation mutants to define the regions required for merlin binding and HRS growth suppression. The HRS domain required for merlin binding was narrowed to residues 470-497 (which contain the predicted coiled-coil domain), and the major domain responsible for HRS growth suppression was localized to residues 498-550. Merlin inhibited growth in Hrs +/+ but not Hrs -/- mouse embryonic fibroblast cells. In contrast, HRS could suppress cell growth in the absence of Nf2 expression. The authors concluded that merlin growth suppression requires HRS expression, and that the binding of merlin to HRS may facilitate its ability to function as a tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444101" 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 transient transfection methods, <a href="#56" class="mim-tip-reference" title="Scoles, D. R., Nguyen, V. D., Qin, Y., Sun, C.-X., Morrison, H., Gutmann, D. H., Pulst, S.-M. <strong>Neurofibromatosis 2 (NF2) tumor suppressor schwannomin and its interacting protein HRS regulate STAT signaling.</strong> Hum. Molec. Genet. 11: 3179-3189, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444102</a>] [<a href="https://doi.org/10.1093/hmg/11.25.3179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12444102">Scoles et al. (2002)</a> showed that both schwannomin and HRS inhibited STAT3 (<a href="/entry/102582">102582</a>) activation, and that schwannomin suppressed STAT3 activation mediated by IGF1 (<a href="/entry/147440">147440</a>) treatment in a human schwannoma cell line. Schwannomin inhibited STAT3 and STAT5 (<a href="/entry/601511">601511</a>) phosphorylation in a rat schwannoma cell line. Schwannomin with the pathogenic missense mutation Q538P (<a href="#0006">607379.0006</a>) failed to bind HRS and did not inhibit STAT5 phosphorylation. The authors hypothesized that schwannomin requires HRS interaction to be fully functionally active and to inhibit STAT activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444102" 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="Scoles, D. R., Chen, M., Pulst, S.-M. <strong>Effects of Nf2 missense mutations on schwannomin interactions.</strong> Biochem. Biophys. Res. Commun. 290: 366-374, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11779178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11779178</a>] [<a href="https://doi.org/10.1006/bbrc.2001.6178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11779178">Scoles et al. (2002)</a> noted that in addition to binding HRS, both of the major isoforms of schwannomin are involved in homodimerization and interact with beta II spectrin (<a href="/entry/182790">182790</a>) and with EIF3S8 (EIF3C; <a href="/entry/603916">603916</a>). Homodimerization and heterodimerization between isoforms occurs through the C-terminal half, as does interaction between schwannomin and HRS and beta II spectrin. Interaction with EIF3S8 occurs through the N-terminal half of schwannomin. Using yeast 2-hybrid assays to characterize further the effect of missense mutations on these interactions, <a href="#54" class="mim-tip-reference" title="Scoles, D. R., Chen, M., Pulst, S.-M. <strong>Effects of Nf2 missense mutations on schwannomin interactions.</strong> Biochem. Biophys. Res. Commun. 290: 366-374, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11779178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11779178</a>] [<a href="https://doi.org/10.1006/bbrc.2001.6178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11779178">Scoles et al. (2002)</a> found that a mutation in the N-terminal half and a mutation in the C-terminal alpha helix significantly decreased dimerization and decreased the affinity between schwannomin and all interacting proteins. Several clinically significant mutations between amino acids 219 and 352 selectively enhanced interactions with their binding partners. <a href="#54" class="mim-tip-reference" title="Scoles, D. R., Chen, M., Pulst, S.-M. <strong>Effects of Nf2 missense mutations on schwannomin interactions.</strong> Biochem. Biophys. Res. Commun. 290: 366-374, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11779178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11779178</a>] [<a href="https://doi.org/10.1006/bbrc.2001.6178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11779178">Scoles et al. (2002)</a> also determined that the sites for schwannomin self-interaction and their binding strengths differ between isoforms 1 and 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11779178" 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 elucidate the properties of merlin that are critical for its tumor suppressor function, <a href="#61" class="mim-tip-reference" title="Stokowski, R. P., Cox, D. R. <strong>Functional analysis of the neurofibromatosis type 2 protein by means of disease-causing point mutations.</strong> Am. J. Hum. Genet. 66: 873-891, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712203</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712203[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/10.1086/302812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712203">Stokowski and Cox (2000)</a> expressed NF2-causing mutant merlin proteins in mammalian cells. They found that 80% of the merlin mutants significantly altered cell adhesion by causing cells to detach from the substratum. They stated that such changes in cell adhesion may be an initial step in the pathogenesis of NF2. In addition, they found that 4 missense mutations decreased the binding of merlin to the ERM-interacting phosphoprotein EBP-50. Some NF2 point mutations resembled dominant gain-of-function rather than loss-of-function alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Fernandez-Valle, C., Tang, Y., Ricard, J., Rodenas-Ruano, A., Taylor, A., Hackler, E., Biggerstaff, J., Iacovelli, J. <strong>Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology.</strong> Nature Genet. 31: 354-362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12118253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12118253</a>] [<a href="https://doi.org/10.1038/ng930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12118253">Fernandez-Valle et al. (2002)</a> noted that mice with conditional deletion of NF2 exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. They found that the molecular adaptor paxillin (<a href="/entry/602505">602505</a>) binds directly to schwannomin in residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (ITGB1; <a href="/entry/135630">135630</a>) and ERBB2 (<a href="/entry/164870">164870</a>). These studies defined a pathogenic mechanism for the development of neurofibromatosis-2 in humans with mutations in exon 2 of NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12118253" 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="Schulze, K. M. M., Hanemann, C. O., Muller, H. W., Hanenburg, H. <strong>Transduction of wild-type merlin into human schwannoma cells decreases schwannoma cell growth and induces apoptosis.</strong> Hum. Molec. Genet. 11: 69-76, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11773000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11773000</a>] [<a href="https://doi.org/10.1093/hmg/11.1.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11773000">Schulze et al. (2002)</a> used oncoretrovirus-mediated gene transfer of different merlin constructs to stably reexpress wildtype merlin in primary cells derived from human schwannomas. Using 2-parameter FACS analysis, they demonstrated that expression of wildtype merlin in NF2 cells led to significant reduction of proliferation and G0/G1 arrest in transduced schwannoma cells. In addition, there was increased apoptosis of schwannoma cells transduced with wildtype merlin. The authors concluded that merlin may act as a tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11773000" 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="Bashour, A.-M., Meng, J.-J., Ip, W., MacCollin, M., Ratner, N. <strong>The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells.</strong> Molec. Cell. Biol. 22: 1150-1157, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11809806[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.22.4.1150-1157.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809806">Bashour et al. (2002)</a> observed that schwannoma-derived Schwann cells exhibited membrane ruffling and aberrant cell spreading when plated onto laminin (see <a href="/entry/150240">150240</a>), indicative of fundamental F-actin cytoskeletal defects. They found that mutations in NF2 correlate with F-actin abnormalities. Using a protein transfer technique with primary human schwannoma cells containing NF2 mutations, they introduced the NF2 protein in an attempt to reverse the cytoskeletal abnormalities. They found that isoform-1 of merlin, the growth-suppressing isoform, reversed the abnormal ruffling and cell spreading and restored normal actin organization. Other isoforms of merlin and merlin containing a point mutation did not reverse the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gautreau, A., Manent, J., Fievet, B., Louvard, D., Giovannini, M., Arpin, M. <strong>Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin-proteasome pathway.</strong> J. Biol. Chem. 277: 31279-31282, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130630</a>] [<a href="https://doi.org/10.1074/jbc.C200125200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130630">Gautreau et al. (2002)</a> noted that the N-terminal FERM domain of schwannomin is implicated in plasma membrane and filamentous actin binding and that mutations in this domain impair proper folding. They found that mutations in the FERM domain were unstable both in vivo and in vitro due to proteasome-mediated degradation. They hypothesized that loss of schwannomin through degradation could contribute to the pathophysiology of NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130630" 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="Shaw, R. J., Paez, J. G., Curto, M., Yaktine, A., Pruitt, W. M., Saotome, I., O'Bryan, J. P., Gupta, V., Ratner, N., Der, C. J., Jacks, T., McClatchey, A. I. <strong>The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling.</strong> Dev. Cell 1: 63-72, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11703924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11703924</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00009-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11703924">Shaw et al. (2001)</a> concluded that NF2 functions in Rac (see <a href="/entry/602048">602048</a>)-dependent signaling. Using electrophoretic mobility shift assays, they identified Rac-induced phosphorylation sites in NF2. They observed that expression of activated Rac-induced phosphorylation of the NF2 serine-518 residue inhibited NF2 self-association and decreased association of NF2 with the cytoskeleton. Using cell transfections, the authors showed that NF2 overexpression inhibited Rac-induced signaling in a phosphorylation-dependent manner. Also, NF2-deficient fibroblasts exhibited characteristics of cells overexpressing activated alleles of Rac. <a href="#60" class="mim-tip-reference" title="Shaw, R. J., Paez, J. G., Curto, M., Yaktine, A., Pruitt, W. M., Saotome, I., O'Bryan, J. P., Gupta, V., Ratner, N., Der, C. J., Jacks, T., McClatchey, A. I. <strong>The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling.</strong> Dev. Cell 1: 63-72, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11703924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11703924</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00009-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11703924">Shaw et al. (2001)</a> hypothesized that NF2 functions as a tumor and metastasis suppressor through its ability to inhibit Rac-dependent signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11703924" 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="Kressel, M., Schmucker, B. <strong>Nucleocytoplasmic transfer of the NF2 tumor suppressor protein merlin is regulated by exon 2 and a CRM1-dependent nuclear export signal in exon 15.</strong> Hum. Molec. Genet. 11: 2269-2278, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12217955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12217955</a>] [<a href="https://doi.org/10.1093/hmg/11.19.2269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12217955">Kressel and Schmucker (2002)</a> showed that splicing out of exon 2 leads to unrestricted entry of merlin into the nucleus, yet skipping of adjacent exon 3 has no comparable effect. Exon 2 functioned as a cytoplasmic retention factor and was able to confer sole cytoplasmic localization to a GFP fusion protein. Merlin's ability to enter the nucleus is complemented by a nuclear-cytoplasmic shuttle protein sequence within exon 15 that facilitates export via the CRM1/exportin pathway. The authors proposed a cellular function different to the wildtype protein for naturally occurring splice variants lacking exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12217955" 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="Jin, H., Sperka, T., Herrlich, P., Morrison, H. <strong>Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase.</strong> Nature 442: 576-579, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885985</a>] [<a href="https://doi.org/10.1038/nature04856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885985">Jin et al. (2006)</a> identified MYPT1 (<a href="/entry/602021">602021</a>) as the enzyme that activates the tumor suppressor function of merlin. The cellular MYPT1-PP1-delta (<a href="/entry/600590">600590</a>)-specific inhibitor CPI17 (<a href="/entry/608153">608153</a>) caused a loss of merlin function characterized by merlin phosphorylation, Ras activation, and transformation. Constitutively active merlin containing the mutation S518A reversed CPI17-induced transformation, showing that merlin is the decisive substrate of MYPT1-PP1-delta in tumor suppression. In addition, <a href="#29" class="mim-tip-reference" title="Jin, H., Sperka, T., Herrlich, P., Morrison, H. <strong>Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase.</strong> Nature 442: 576-579, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885985</a>] [<a href="https://doi.org/10.1038/nature04856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885985">Jin et al. (2006)</a> showed that CPI17 levels are raised in several human tumor cell lines and that the downregulation of CPI17 induces merlin dephosphorylation, inhibits Ras activation, and abolishes the transformed phenotype. <a href="#29" class="mim-tip-reference" title="Jin, H., Sperka, T., Herrlich, P., Morrison, H. <strong>Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase.</strong> Nature 442: 576-579, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885985</a>] [<a href="https://doi.org/10.1038/nature04856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885985">Jin et al. (2006)</a> concluded that MYPT1 and its substrate merlin are part of a previously undescribed tumor suppressor cascade that can be hindered in 2 ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16885985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By reciprocal yeast 2-hybrid and coimmunoprecipitation analyses of the human STS26T malignant schwannoma cell line, <a href="#57" class="mim-tip-reference" title="Scoles, D. R., Yong, W. H., Qin, Y., Wawrowsky, K., Pulst, S. M. <strong>Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (elF3c).</strong> Hum. Molec. Genet. 15: 1059-1070, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16497727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16497727</a>] [<a href="https://doi.org/10.1093/hmg/ddl021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16497727">Scoles et al. (2006)</a> showed that isoforms 1 and 2 of schwannomin interacted with EIF3C, a subunit of eukaryotic initiation factor-3 (EIF3). Mutation analysis revealed that the FERM domain of schwannomin interacted with the C-terminal half of EIF3C. Immunofluorescence microscopy of STS26T cells showed that the 2 proteins partly colocalized at punctate perinuclear structures and at some membranous structures. Overexpression of EIF3C in STS26T cells elevated cell proliferation, and schwannomin countered this effect. Western blot analysis revealed an inverse abundance of schwannomin and EIF3C in human meningiomas. <a href="#57" class="mim-tip-reference" title="Scoles, D. R., Yong, W. H., Qin, Y., Wawrowsky, K., Pulst, S. M. <strong>Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (elF3c).</strong> Hum. Molec. Genet. 15: 1059-1070, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16497727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16497727</a>] [<a href="https://doi.org/10.1093/hmg/ddl021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16497727">Scoles et al. (2006)</a> concluded that schwannomin functions as a tumor suppressor by inhibiting EIF3-mediated initiation of protein translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16497727" 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="#14" class="mim-tip-reference" title="Curto, M., McClatchey, A. <strong>Nf2/Merlin: a coordinator of receptor signalling and intercellular contact.</strong> Brit. J. Cancer 98: 256-262, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17971776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17971776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17971776[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.6604002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17971776">Curto and McClatchey (2008)</a> reviewed the mechanisms by which NF2 regulates contact-dependent inhibition of proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17971776" 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="#68" class="mim-tip-reference" title="Wu, J., Minikes, A. M., Gao, M., Bian, H., Li, Y., Stockwell, B. R., Chen, Z.-N., Jiang, X. <strong>Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling.</strong> Nature 572: 402-406, 2019. Note: Erratum Nature 572: E20, 2019. Electronic Publication.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31341276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31341276</a>] [<a href="https://doi.org/10.1038/s41586-019-1426-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31341276">Wu et al. (2019)</a> showed that ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin (<a href="/entry/192090">192090</a>) suppress ferroptosis by activating the intracellular NF2 and Hippo signaling pathway. Antagonizing this signaling axis allowed the protooncogenic transcriptional coactivator YAP (<a href="/entry/606608">606608</a>) to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 (<a href="/entry/300157">300157</a>) and TFRC (<a href="/entry/190010">190010</a>). This finding provided mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis. Notably, a similar mechanism also modulated ferroptosis in some nonepithelial cells. Finally, genetic inactivation of the tumor suppressor NF2, a frequent tumorigenic event in mesothelioma, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. <a href="#68" class="mim-tip-reference" title="Wu, J., Minikes, A. M., Gao, M., Bian, H., Li, Y., Stockwell, B. R., Chen, Z.-N., Jiang, X. <strong>Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling.</strong> Nature 572: 402-406, 2019. Note: Erratum Nature 572: E20, 2019. Electronic Publication.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31341276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31341276</a>] [<a href="https://doi.org/10.1038/s41586-019-1426-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31341276">Wu et al. (2019)</a> concluded that their results demonstrated the role of intercellular interactions and intracellular NF2-YAP signaling in dictating ferroptotic death, and also suggested that malignant mutations in NF2-YAP signaling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31341276" 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="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> provided incontrovertible evidence that the NF2 gene is the site of the mutations causing neurofibromatosis-2 (NF2), now called vestibular schwannomatosis (SWNV; <a href="/entry/101000">101000</a>), by demonstrating germline and somatic SCH mutations in NF2 patients and in NF2-related tumors. They found 16 mutations, 15 of which were predicted to result in truncated proteins (see <a href="#0001">607379.0001</a> and <a href="#0002">607379.0002</a>). Consistent with the classic Knudson theory of tumor suppressor genes, loss of the wildtype allele at the NF2 locus was demonstrated in 6 of 8 tumors containing NF2 mutations (<a href="#63" class="mim-tip-reference" title="Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munroe, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., Gusella, J. F. <strong>A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.</strong> Cell 72: 791-800, 1993. Note: Erratum: Cell 75: 826 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8453669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8453669</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90406-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8453669">Trofatter et al., 1993</a>; <a href="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al., 1993</a>). For example, in a meningioma in a patient without features of NF2, they found deletion of 2 nucleotides, TC, from codon 61 resulting in a frameshift; the normal allele on the other chromosome had been lost. In 2 instances of schwannoma occurring in patients without evidence of NF2, <a href="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> found nonsense mutations that were absent in the patient's blood DNA; in these instances also the normal allele had been lost. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8453669+8379998" 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>Most of the mutations in NF2 cause the synthesis of a truncated schwannomin protein. After examining 8 of the 16 known NF2 exons in 151 meningiomas, <a href="#50" class="mim-tip-reference" title="Ruttledge, M. H., Sarrazin, J., Rangaratnam, S., Phelan, C. M., Twist, E., Merel, P., Delattre, O., Thomas, G., Nordenskjold, M., Collins, V. P., Dumanski, J. P., Rouleau, G. A. <strong>Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas.</strong> Nature Genet. 6: 180-184, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162072</a>] [<a href="https://doi.org/10.1038/ng0294-180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162072">Ruttledge et al. (1994)</a> characterized 24 inactivating mutations. Significantly, these aberrations were detected exclusively in tumors that had lost the other chromosome 22 allele. These results provided strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene. The same group had found loss of heterozygosity (LOH) for polymorphic DNA markers flanking NF2 on chromosome 22 in 102 (60%) of 170 primary sporadic meningiomas. Thus, another gene may be involved in the development of 40% of meningiomas. All 24 of the inactivating mutations found by <a href="#50" class="mim-tip-reference" title="Ruttledge, M. H., Sarrazin, J., Rangaratnam, S., Phelan, C. M., Twist, E., Merel, P., Delattre, O., Thomas, G., Nordenskjold, M., Collins, V. P., Dumanski, J. P., Rouleau, G. A. <strong>Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas.</strong> Nature Genet. 6: 180-184, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162072</a>] [<a href="https://doi.org/10.1038/ng0294-180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162072">Ruttledge et al. (1994)</a> in sporadic meningiomas were nonsense, frameshift (due to small deletions), or splice site mutations; there were no missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162072" 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="#51" class="mim-tip-reference" title="Sainz, J., Huynh, D. P., Figueroa, K., Ragge, N. K., Baser, M. E., Pulst, S.-M. <strong>Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas.</strong> Hum. Molec. Genet. 3: 885-891, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951231</a>] [<a href="https://doi.org/10.1093/hmg/3.6.885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951231">Sainz et al. (1994)</a> performed mutation analysis in 30 vestibular schwannomas and found 18 mutations in NF2, 7 of which contained loss or mutation of both alleles. Most mutations predicted a truncated protein. Mutation hotspots were not identified. Only 1 of the mutations was in a tumor from a patient with NF2. Immunocytochemical studies using antibodies to the NF2 protein showed complete absence of staining in tumor Schwann cells, whereas staining was observed in normal vestibular nerve. These data indicated that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene. In studies of 34 vestibular schwannomas and 14 schwannomas at other locations, <a href="#9" class="mim-tip-reference" title="Bijlsma, E. K., Merel, P., Bosch, D. A., Westerveld, A., Delattre, O., Thomas, G., Hulsebos, T. J. M. <strong>Analysis of mutations in the SCH gene in schwannomas.</strong> Genes Chromosomes Cancer 11: 7-14, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7529050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7529050</a>] [<a href="https://doi.org/10.1002/gcc.2870110103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7529050">Bijlsma et al. (1994)</a> found that the SCH gene is implicated in the development of these tumors in all locations of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7529050+7951231" 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="#7" class="mim-tip-reference" title="Bianchi, A. B., Hara, T., Ramesh, V., Gao, J., Klein-Szanto, A. J. P., Morin, F., Menon, A. G., Trofatter, J. A., Gusella, J. F., Seizinger, B. R., Kley, N. <strong>Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types.</strong> Nature Genet. 6: 185-192, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162073</a>] [<a href="https://doi.org/10.1038/ng0294-185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162073">Bianchi et al. (1994)</a> described a novel isoform of the NF2 transcript that shows differential tissue expression and encodes a modified C terminus of the predicted protein. Mutations affecting both isoforms of the NF2 transcript were detected in multiple tumor types including melanoma and breast carcinoma. These findings provided evidence that alterations in the NF2 transcript occurred not only in the hereditary brain neoplasms typically associated with NF, but also as somatic mutations in their sporadic counterparts and in seemingly unrelated tumor types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162073" 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 screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence, <a href="#41" class="mim-tip-reference" title="Merel, P., Hoang-Xuan, K., Sanson, M., Moreau-Aubry, A., Bijlsma, E. K., Lazaro, C., Moisan, J. P., Resche, F., Nishisho, I., Estivill, X., Delattre, J. Y., Poisson, M., Theillet, C., Hulsebos, T., Delattre, O., Thomas, G. <strong>Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas.</strong> Genes Chromosomes Cancer 13: 211-216, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669741</a>] [<a href="https://doi.org/10.1002/gcc.2870130311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669741">Merel et al. (1995)</a> observed mutations in 17 of 57 meningiomas and in 30 of 89 schwannomas. All of the meningiomas and half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. No mutations were observed in 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. This led <a href="#41" class="mim-tip-reference" title="Merel, P., Hoang-Xuan, K., Sanson, M., Moreau-Aubry, A., Bijlsma, E. K., Lazaro, C., Moisan, J. P., Resche, F., Nishisho, I., Estivill, X., Delattre, J. Y., Poisson, M., Theillet, C., Hulsebos, T., Delattre, O., Thomas, G. <strong>Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas.</strong> Genes Chromosomes Cancer 13: 211-216, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669741</a>] [<a href="https://doi.org/10.1002/gcc.2870130311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669741">Merel et al. (1995)</a> to conclude that the involvement of the NF2 gene is restricted to schwannomas and meningiomas, where it is frequently inactivated by a 2-hit process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7669741" 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="#65" class="mim-tip-reference" title="Wellenreuther, R., Kraus, J. A., Lenartz, D., Menon, A. G., Schramm, J., Louis, D. N., Ramesh, V., Gusella, J. F., Wiestler, O. D., von Deimling, A. <strong>Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma.</strong> Am. J. Path. 146: 827-832, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717450</a>]" pmid="7717450">Wellenreuther et al. (1995)</a> likewise concluded that NF2 represents the meningioma locus on chromosome 22. There was a significant association of loss of heterozygosity on chromosome 22 with mutations in the NF2 gene. They analyzed the entire coding region of the NF2 gene in 70 sporadic meningiomas and identified 43 mutations in 41 patients. These resulted predominantly in immediate truncation, splicing abnormalities, or an altered reading frame of the predicted protein product. All mutations occurred in the first 13 exons, the region of homology with the filopodial proteins moesin, ezrin, and radixin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7717450" 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="#69" class="mim-tip-reference" title="Zucman-Rossi, J., Legoix, P., Der Sarkissian, H., Cheret, G., Sor, F., Bernardi, A., Cazes, L., Giraud, S., Ollagnon, E., Lenoir, G., Thomas, G. <strong>NF2 gene in neurofibromatosis type 2 patients.</strong> Hum. Molec. Genet. 7: 2095-2101, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817927</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817927">Zucman-Rossi et al. (1998)</a> noted that although penetrance of neurofibromatosis II is greater than 95% and no genetic heterogeneity has been described, point mutations in the NF2 gene have been observed in only 34 to 66% of screened NF2 patients in various series. They deduced the entire genomic sequence of the NF2 gene and undertook a mutation screening strategy that, when applied to a series of 19 NF2 patients, revealed a high recurrence of large deletions in the gene and raised the efficiency of mutation detection in NF2 patients to 84% of the cases in this series. The remaining 3 patients who expressed 2 functional NF2 alleles were all sporadic cases, an observation compatible with the presence of mosaicism for NF2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817927" 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="#39" class="mim-tip-reference" title="Legoix, P., Legrand, M.-F., Ollagnon, E., Lenoir, G., Thomas, G., Zucman-Rossi, J. <strong>Characterisation of 16 polymorphic markers in the NF2 gene: application to hemizygosity detection.</strong> Hum. Mutat. 13: 290-293, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220142</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<290::AID-HUMU5>3.0.CO;2-C" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220142">Legoix et al. (1999)</a> estimated that about 50% of NF2 patients show point mutations in the NF2 gene, and that large genomic deletions account for approximately one-third of NF2 gene alterations. To facilitate deletion screening, they identified 16 polymorphic markers in the NF2 genomic sequence, enabling a hemizygosity test in familial studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220142" 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="#32" class="mim-tip-reference" title="Kluwe, L., Friedrich, R. E., Hagel, C., Lindenau, M., Mautner, V.-F. <strong>Mutations and allelic loss of the NF2 gene in neurofibromatosis 2-associated skin tumors.</strong> J. Invest. Derm. 114: 1017-1021, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10771486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10771486</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2000.00975.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10771486">Kluwe et al. (2000)</a> studied 40 skin tumors (36 schwannomas and 4 neurofibromas) from 20 NF2 patients, 15 of whom had NF2 mutations previously identified in blood leukocytes. The detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%). They found NF2 mutations in 5 tumors (13%) and NF2 allelic loss in 18 (45%) of the 40 examined tumors. Alterations in both NF2 alleles were found in 17 (43%) of the tumors. They concluded that loss of a functional NF2 gene product is a critical event in the generation of skin schwannomas and that mutation detection in skin tumors may be a useful diagnostic tool in patients with skin tumors where the clinical diagnosis of NF2 is ambiguous, or in unclear cases in which NF1 must be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10771486" 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="#64" class="mim-tip-reference" title="Tsilchorozidou, T., Menko, F. H., Lalloo, F., Kidd, A., De Silva, R., Thomas, H., Smith, P., Malcolmson, A., Dore, J., Madan, K., Brown, A., Yovos, J. G., Tsaligopoulos, M., Vogiatzis, N., Baser, M. E., Wallace, A. J., Evans, D. G. R. <strong>Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2. (Letter)</strong> J. Med. Genet. 41: 529-534, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235024</a>] [<a href="https://doi.org/10.1136/jmg.2003.016774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235024">Tsilchorozidou et al. (2004)</a> reported 5 NF2 patients with constitutional rearrangements of chromosome 22 and vestibular schwannomas, multiple intracranial meningiomas, and spinal tumors. The authors noted that an additional 10 NF2 patients with constitutional NF2 deletions had been discovered using NF2 FISH in their laboratory, and suggested that chromosome analysis with FISH might be a useful first screen prior to molecular testing in NF2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235024" 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="Kluwe, L., Mautner, V., Parry, D. M., Jacoby, L. B., Baser, M., Gusella, J., Davis, K., Stavrou, D., MacCollin, M. <strong>The parental origin of new mutations in neurofibromatosis 2.</strong> Neurogenetics 3: 17-24, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085592</a>] [<a href="https://doi.org/10.1007/s100480000088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11085592">Kluwe et al. (2000)</a> studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In 45 informative individuals, 31 mutations (69%) were of paternal origin and 14 (31%) of maternal origin. In 4 of 6 patients with somatic mosaicism, the NF2 mutation was of maternal origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ahronowitz, I., Xin, W., Kiely, R., Sims, K., MacCollin, M., Nunes, F. P. <strong>Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.</strong> Hum. Mutat. 28: 1-12, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16983642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16983642</a>] [<a href="https://doi.org/10.1002/humu.20393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16983642">Ahronowitz et al. (2007)</a> presented a metaanalysis of 967 constitutional and somatic NF2 alterations from 93 published reports, along with 59 additional unpublished mutations identified in their laboratory and 115 alterations identified in clinical samples submitted to the Neurogenetics DNA Diagnostic Laboratory of the Massachusetts General Hospital. In total, these sources defined 1,070 small genetic changes detected primarily by exon scanning, 42 intragenic changes of 1 whole exon or larger, and 29 whole gene deletions and gross chromosomal rearrangements. Overall, somatic events showed a significantly different genetic profile than constitutional events. Somatic events were strongly skewed toward frameshift (accounting for over one-half of these mutations) in comparison to constitutional changes that were primarily nonsense and splice site, as had been previously described by <a href="#3" class="mim-tip-reference" title="Baser, M. E., Contributors to the International NF2 Mutation Database. <strong>The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene.</strong> Hum. Mutat. 27: 297-306, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16521120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16521120</a>] [<a href="https://doi.org/10.1002/humu.20317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16521120">Baser and Contributors to the International NF2 Mutation Database (2006)</a>. Somatic events also differed markedly between tumors of different pathology, most significantly in the tendency of somatic events in meningiomas to lie within the 5-prime FERM domain of the transcript with a complete absence of mutations in exons 14 and 15. Less than 10% of all published and unpublished small alterations were nontruncating and these changes were clustered in exons 2 and 3, suggesting that this region may be especially crucial to tumor suppressor activity in the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16521120+16983642" 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>Somatic Mosaicism</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Evans, D. G. R., Wallace, A. J., Wu, C. L., Trueman, L., Ramsden, R. T., Strachan, T. <strong>Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis.</strong> Am. J. Hum. Genet. 63: 727-736, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9718334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9718334</a>] [<a href="https://doi.org/10.1086/512074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9718334">Evans et al. (1998)</a> sought mutations in the NF2 gene in 125 families with classic NF2 with bilateral vestibular schwannomas; causative mutations were identified in 52 families. In 5 families, the first affected individual in the family was a mosaic for a disease-causing mutation. Only 1 of the 9 children from the 3 mosaic cases with children were affected. Four of these 9 children inherited the allele associated with the disease-causing mutation yet did not inherit the mutation. NF2 mutations were identified in only 27 of 79 (34%) sporadic cases, compared with 25 of 46 (54%) familial cases (P less than 0.05). In 48 families in which a mutation had not been identified, the index cases had 125 children, of whom only 29 were affected with NF2 and of whom only a further 21 cases would be predicted to be affected by use of life curves. The 50 of 125 (40%) cases is significantly less than the 50% expected eventually to develop NF2 (P less than 0.05). Somatic mosaicism is likely to be a common cause of classic NF2 and may well account for a low detection rate for mutations in sporadic cases. Degrees of gonosomal mosaicism mean that recurrence risks may well be less than 50% in the offspring of the index case when a mutation was not identified in lymphocyte DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9718334" 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="#36" class="mim-tip-reference" title="Kluwe, L., Mautner, V.-F. <strong>Mosaicism in sporadic neurofibromatosis 2 patients.</strong> Hum. Molec. Genet. 7: 2051-2055, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817921</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817921">Kluwe and Mautner (1998)</a> concluded that mosaicism is relatively common in NF2, with important implications for diagnosis, prognosis, and genetic counseling. In 4 sporadic NF2 patients, they found NF2 mutations in only a portion of leukocytes. In 2 other sporadic patients, no mutations were found in leukocytes but constitutional NF2 mutations were suggested by the finding of identical mutations in different tumors from each patient. <a href="#36" class="mim-tip-reference" title="Kluwe, L., Mautner, V.-F. <strong>Mosaicism in sporadic neurofibromatosis 2 patients.</strong> Hum. Molec. Genet. 7: 2051-2055, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817921</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817921">Kluwe and Mautner (1998)</a> screened leukocyte DNA from a total of 16 inherited and 91 sporadic NF2 patients, and found NF2 mutations in 13 (81%) of the former and in 46 (51%) of the latter cases. They suspected that the 30% difference in the rate of detection of mutations might be partially explained by mosaicism in a portion of sporadic NF2 patients who carry the mutations in such a fashion that their leukocytes are unaffected. Among sporadic cases, they found mutations to be more frequent in patients with severe phenotypes (59%) than in patients with mild phenotypes (23%). This likewise might be explained by mosaicism, with the smaller population of mutation-bearing cells resulting in mild phenotypes. No mutations were found in 8 patients suspected of having NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817921" 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="#59" class="mim-tip-reference" title="Sestini, R., Vivarelli, R., Balestri, P., Ammannati, F., Montali, E., Papi, L. <strong>Neurofibromatosis type 2 attributable to gonosomal mosaicism in a clinically normal mother, and identification of seven novel mutations in the NF2 gene.</strong> Hum. Genet. 107: 366-371, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11129337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11129337</a>] [<a href="https://doi.org/10.1007/s004390000378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11129337">Sestini et al. (2000)</a> reported the genetic study of 33 NF2 patients from 33 unrelated Italian families. Twelve mutations were characterized, including 7 newly identified mutations and 5 recurrent ones. Furthermore, they described 1 patient with an inactivating mutation in exon 13 present in only a portion of the lymphocytes and, more importantly, a clinically normal individual carrying a somatic/germinal mosaicism for a nonsense mutation in exon 10 of the NF2 gene. The results confirmed the relatively high percentage of mosaicism for mutations in the NF2 gene and established the importance of evaluating genomic DNA from several tissues, in addition to lymphocytes, so as to identify mosaicism in 'de novo' NF2 patients and their relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11129337" 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="Moyhuddin, A., Baser, M. E., Watson, C., Purcell, S., Ramsden, R. T., Heiberg, A., Wallace, A. J., Evans, D. G. R. <strong>Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring.</strong> J. Med. Genet. 40: 459-463, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12807969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12807969</a>] [<a href="https://doi.org/10.1136/jmg.40.6.459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12807969">Moyhuddin et al. (2003)</a> described mutation analysis of 27 mosaic cases of NF2 and the results of genetic testing in their children. They estimated that 30% of de novo NF2 patients are mosaic. The authors suggested that mosaicism should be suspected in a mildly affected isolated patient with no mutation detected in blood. Risk of transmission to offspring is small in an NF2 patient with a mutation detectable only in tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12807969" 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="Kluwe, L., Mautner, V., Heinrich, B., Dezube, R., Jacoby, L. B., Friedrich, R. E., MacCollin, M. <strong>Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas.</strong> J. Med. Genet. 40: 109-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566519</a>] [<a href="https://doi.org/10.1136/jmg.40.2.109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566519">Kluwe et al. (2003)</a> identified mutations in the NF2 gene in peripheral blood of 122 of 233 (52%) NF2 founders (those with clinically unaffected parents). Mutations in the NF2 gene were identified in 21 of 35 available tumor specimens from the 111 patients who did not have detectable peripheral blood mutations. Nine of these patients had a constitutional mutation which was also found in distinct second tumors. <a href="#33" class="mim-tip-reference" title="Kluwe, L., Mautner, V., Heinrich, B., Dezube, R., Jacoby, L. B., Friedrich, R. E., MacCollin, M. <strong>Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas.</strong> J. Med. Genet. 40: 109-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566519</a>] [<a href="https://doi.org/10.1136/jmg.40.2.109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566519">Kluwe et al. (2003)</a> concluded that failure to find NF2 mutations in peripheral blood of NF2 mutations was due to somatic mosaicism. By extrapolation, the authors estimated that the rate of somatic mosaicism in their cohort was 24.8%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566519" 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>Schwannomatosis</em></strong></p><p>
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Neurilemmomatosis (<a href="/entry/162091">162091</a>), also called schwannomatosis, first reported by <a href="#44" class="mim-tip-reference" title="Niimura, M. <strong>Neurofibromatosis.</strong> Rinsho Derma 15: 653-663, 1973."None>Niimura (1973)</a> as neurofibromatosis type 3, is characterized by multiple cutaneous neurilemmomas and spinal schwannomas, without acoustic tumors or other signs of NF1 or NF2. In neurilemmomas, the tumor consists of Schwann cells. <a href="#27" class="mim-tip-reference" title="Honda, M., Arai, E., Sawada, S., Ohta, A., Niimura, M. <strong>Neurofibromatosis 2 and neurilemmomatosis gene are identical.</strong> J. Invest. Derm. 104: 74-77, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7798645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7798645</a>] [<a href="https://doi.org/10.1111/1523-1747.ep12613537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7798645">Honda et al. (1995)</a> analyzed the peripheral leukocytes and tissue from cutaneous neurilemmomas of 7 patients with neurilemmomatosis using DNA markers for different regions of chromosome 22. They detected allele losses in 3 of 7 tumors from 7 patients with a probe for the NF2 region and the germline mutations in 2 of 3 tumors from the same 3 patients. They described 2 mutations in the NF2 gene (<a href="#0017">607379.0017</a>; <a href="#0018">607379.0018</a>). They concluded that neurilemmomatosis is a form of NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7798645" 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="Jacoby, L. B., Jones, D., Davis, K., Kronn, D., Short, M. P., Gusella, J., MacCollin, M. <strong>Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis.</strong> Am. J. Hum. Genet. 61: 1293-1302, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9399891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9399891</a>] [<a href="https://doi.org/10.1086/301633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9399891">Jacoby et al. (1997)</a> investigated the molecular genetic basis of schwannomatosis in patients with multiple schwannomas without vestibular schwannomas, which has been postulated to represent a distinct subclass of neurofibromatosis. They found the unusual situation that in studies of 20 unrelated schwannomatosis patients and their affected relatives, tumors from the patients frequently harbored typical truncating mutations of the NF2 gene and loss of heterozygosity of the surrounding region of chromosome 22. Surprisingly, unlike patients with NF2, no heterozygous NF2 gene changes were seen in normal tissues. Furthermore, examination of multiple tumors from the same patients revealed that some schwannomatosis patients are somatic mosaics for NF2 gene changes. By contrast, other individuals, particularly those with a positive family history, appeared to have an inherited predisposition to formation of tumors that carry somatic alterations of the NF2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9399891" 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 7 tumor specimens resected from a 36-year-old man with schwannomatosis, <a href="#30" class="mim-tip-reference" title="Kaufman, D. L., Heinrich, B. S., Willett, C., Perry, A., Finseth, F., Sobel, R. A., MacCollin, M. <strong>Somatic instability of the NF2 gene in schwannomatosis.</strong> Arch. Neurol. 60: 1317-1320, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12975302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12975302</a>] [<a href="https://doi.org/10.1001/archneur.60.9.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12975302">Kaufman et al. (2003)</a> found LOH at the NF2 locus in all tumors, and in every case the same allele was lost, implying that somatic mutations accumulate on the same retained allele. Four of the specimens contained unrelated truncating mutations of the NF2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12975302" 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="Sestini, R., Bacci, C., Provenzano, A., Genuardi, M., Papi, L. <strong>Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas.</strong> Hum. Mutat. 29: 227-231, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18072270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18072270</a>] [<a href="https://doi.org/10.1002/humu.20679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18072270">Sestini et al. (2008)</a> identified somatic mutations in the NF2 gene in tumor tissue derived from 3 unrelated patients with schwannomatosis. LOH was also observed in all cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18072270" 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>Malignant Mesothelioma</em></strong></p><p>
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Malignant mesotheliomas (MMs; <a href="/entry/156240">156240</a>) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations had been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. This prompted <a href="#8" class="mim-tip-reference" title="Bianchi, A. B., Mitsunaga, S.-I., Cheng, J. Q., Klein, W. M., Jhanwar, S. C., Seizinger, B., Kley, N., Klein-Szanto, A. J. P., Testa, J. R. <strong>High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas.</strong> Proc. Nat. Acad. Sci. 92: 10854-10858, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7479897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7479897</a>] [<a href="https://doi.org/10.1073/pnas.92.24.10854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7479897">Bianchi et al. (1995)</a> to investigate the status of the NF2 gene in these tumors. In studies of cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors, NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in 8 cell lines (53%), 6 of which were confirmed in primary tumor DNAs. In 2 samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. Unlike previously described NF2-related tumors, MM derived from the mesoderm; malignancies of this origin had not previously been associated with frequent alterations of the NF2 gene. In a commentary in the same journal issue, <a href="#37" class="mim-tip-reference" title="Knudson, A. <strong>Asbestos and mesothelioma: genetic lessons from a tragedy.</strong> Proc. Nat. Acad. Sci. 92: 10819-10820, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7479890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7479890</a>] [<a href="https://doi.org/10.1073/pnas.92.24.10819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7479890">Knudson (1995)</a> wrote: 'We are left wondering why mesothelioma is not a feature of the hereditary disease NF2.' <a href="#4" class="mim-tip-reference" title="Baser, M. E., De Rienzo, A., Altomare, D., Balsara, B. R., Hedrick, N. M., Gutmann, D. H., Pitts, L. H., Jackler, R. K., Testa, J. R. <strong>Neurofibromatosis 2 and malignant mesothelioma.</strong> Neurology 59: 290-291, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136076</a>] [<a href="https://doi.org/10.1212/wnl.59.2.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136076">Baser et al. (2002)</a> reported a patient with NF2 who developed malignant mesothelioma after a long occupational exposure to asbestos. Genetic analysis of the tumor tissue showed loss not only of chromosome 22 but also of chromosomes 14 and 15, and gain of chromosome 7. <a href="#4" class="mim-tip-reference" title="Baser, M. E., De Rienzo, A., Altomare, D., Balsara, B. R., Hedrick, N. M., Gutmann, D. H., Pitts, L. H., Jackler, R. K., Testa, J. R. <strong>Neurofibromatosis 2 and malignant mesothelioma.</strong> Neurology 59: 290-291, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136076</a>] [<a href="https://doi.org/10.1212/wnl.59.2.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136076">Baser et al. (2002)</a> suggested that an individual with a constitutional mutation of an NF2 allele, as in NF2, is more susceptible to mesothelioma. Although mesothelioma is not a common feature in NF2, the authors cited the observation of <a href="#37" class="mim-tip-reference" title="Knudson, A. <strong>Asbestos and mesothelioma: genetic lessons from a tragedy.</strong> Proc. Nat. Acad. Sci. 92: 10819-10820, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7479890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7479890</a>] [<a href="https://doi.org/10.1073/pnas.92.24.10819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7479890">Knudson (1995)</a> that somatic mutations of a tumor suppressor gene, such as NF2, RB1 (<a href="/entry/614041">614041</a>), or p53 (<a href="/entry/191170">191170</a>), can be common in a tumor type that is not characteristic of the hereditary disorder, perhaps due to the proliferative timing of the cells involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12136076+7479890+7479897" 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="#19" class="mim-tip-reference" title="Fleury-Feith, J., Lecomte, C., Renier, A., Matrat, M., Kheuang, L., Abramowski, V., Levy, F., Janin, A., Giovannini, M., Jaurand, M.-C. <strong>Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours.</strong> Oncogene 22: 3799-3805, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12802287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12802287</a>] [<a href="https://doi.org/10.1038/sj.onc.1206593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12802287">Fleury-Feith et al. (2003)</a> noted that biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. To assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibers, they investigated the NF2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene, after intraperitoneal inoculation of crocidolite fibers. Asbestos-exposed mice heterozygous for a knockout of Nf2 developed tumoral ascites and mesothelioma at higher frequency than their wildtype counterparts (P less than 0.05). Six out of 7 mesothelioma cell lines established from neoplastic ascitic fluids of these heterozygous knockout mice exhibited loss of the wildtype Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results showed the importance of the Nf2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumor suppressor gene inactivation, and suggested that NF2 gene mutation may be a susceptibility factor to asbestos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12802287" 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="#46" class="mim-tip-reference" title="Parry, D. M., MacCollin, M. M., Kaiser-Kupfer, M. I., Pulaski, K., Nicholson, H. S., Bolesta, M., Eldridge, R., Gusella, J. F. <strong>Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.</strong> Am. J. Hum. Genet. 59: 529-539, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8751853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8751853</a>]" pmid="8751853">Parry et al. (1996)</a> used SSCP analysis to screen for mutations in DNA from 32 unrelated NF2 patients. Mutations were identified in 66% of patients and 20 different mutations were found in 21 patients. They suggested that their results confirmed the association between nonsense and frameshift mutations and clinical manifestations compatible with severe disease. They stated that their data raised questions regarding the role of other factors, in addition to the intrinsic properties of individual mutations, that might influence the phenotype. <a href="#49" class="mim-tip-reference" title="Ruttledge, M. H., Andermann, A. A., Phelan, C. M., Claudio, J. O., Han, F., Chretien, N., Rangaratnam, S., MacCollin, M., Short, P., Parry, D., Michels, V., Riccardi, V. M., Weksberg, R., Kitamura, K., Bradburn, J. M., Hall, B. D., Propping, P., Rouleau, G. A. <strong>Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease.</strong> Am. J. Hum. Genet. 59: 331-342, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755919</a>]" pmid="8755919">Ruttledge et al. (1996)</a> reported that when individuals harboring protein-truncating mutations are compared with patients having single codon alterations, a significant correlation (p less than 0.001) with clinical outcome is observed. They noted that 24 of 28 patients with mutations that cause premature termination of the NF2 protein presented with severe phenotypes. In contrast, all 16 cases from 3 families with mutations that affect only a single amino acid had mild NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8755919+8751853" 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="Evans, D. G. R., Trueman, L., Wallace, A., Collins, S., Strachan, T. <strong>Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.</strong> J. Med. Genet. 35: 450-455, 1998. Note: Erratum: J. Med. Genet. 36: 86 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9643284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9643284</a>] [<a href="https://doi.org/10.1136/jmg.35.6.450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9643284">Evans et al. (1998)</a> reported 42 cases of NF2 from 38 families with truncating mutations. The average age of onset of symptoms was 19 years and age at diagnosis 22.4 years. Fifty-one cases from 16 families (15 with splice site mutations, 18 with missense mutations, and 18 with large deletions) had an average age of onset of 27.8 years and age at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to develop symptoms before 20 years of age (p less than 0.001) and to develop at least 2 symptomatic CNS tumors in addition to vestibular schwannoma before 30 years (p less than 0.001). There were significantly fewer multigenerational families with truncating mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9643284" 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="Kehrer-Sawatzki, H., Udart, M., Krone, W., Baden, R., Fahsold, R., Thomas, G., Schmucker, B., Assum, G. <strong>Mutational analysis and expression studies of the neurofibromatosis type 2 (NF2) gene in a patient with a ring chromosome 22 and NF2.</strong> Hum. Genet. 100: 67-74, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225971</a>] [<a href="https://doi.org/10.1007/s004390050467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225971">Kehrer-Sawatzki et al. (1997)</a> reported a patient with NF2 and a ring chromosome 22 (46,XX,r(22)/45,XX,-22). Severe manifestations included multiple meningiomas, spinal and peripheral neurinomas, and bilateral vestibular schwannomas. The patient was also severely mentally retarded, a feature not usually associated with NF2. The authors hypothesized that a mutation in the NF2 gene of the normal chromosome 22, in addition to the loss of the ring 22 in many cells during mitosis, could explain the presence of multiple tumors. Using a meningioma cell line lacking the ring chromosome, <a href="#31" class="mim-tip-reference" title="Kehrer-Sawatzki, H., Udart, M., Krone, W., Baden, R., Fahsold, R., Thomas, G., Schmucker, B., Assum, G. <strong>Mutational analysis and expression studies of the neurofibromatosis type 2 (NF2) gene in a patient with a ring chromosome 22 and NF2.</strong> Hum. Genet. 100: 67-74, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225971</a>] [<a href="https://doi.org/10.1007/s004390050467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225971">Kehrer-Sawatzki et al. (1997)</a> searched for deletions, rearrangements, or other mutations of the NF2 gene on the normal chromosome 22; no such alterations were found. The authors concluded that the loss of the entire chromosome 22 and its multiple tumor suppressor genes may have led to the severe phenotype in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9225971" 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="#11" class="mim-tip-reference" title="Bruder, C. E. G., Hirvela, C., Tapia-Paez, I., Fransson, I., Segraves, R., Hamilton, G., Zhang, X. X., Evans, D. G., Wallace, A. J., Baser, M. E., Zucman-Rossi, J., Hergersberg, M., and 22 others. <strong>High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.</strong> Hum. Molec. Genet. 10: 271-282, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159946</a>] [<a href="https://doi.org/10.1093/hmg/10.3.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159946">Bruder et al. (2001)</a> examined the 7-Mb interval in the vicinity of the NF2 gene in a series of 116 NF2 patients in order to determine the frequency and extent of deletions. Using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of the region around the NF2 locus, deletions of various sizes were detected in 8 severe, 10 moderate, and 6 mild patients. This result did not support a correlation between the type of mutation affecting the NF2 gene and the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159946" 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 831 patients from 528 NF2 families, <a href="#5" class="mim-tip-reference" title="Baser, M. E., Kuramoto, L., Woods, R., Joe, H., Friedman, J. M., Wallace, A. J., Ramsden, R. T., Olschwang, S., Bijlsma, E., Kalamarides, M., Papi, L., Kato, R., Carroll, J., Lazaro, C., Joncourt, F., Parry, D. M., Rouleau, G. A., Evans, D. G. R. <strong>The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2.</strong> J. Med. Genet. 42: 540-546, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15994874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15994874</a>] [<a href="https://doi.org/10.1136/jmg.2004.029504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15994874">Baser et al. (2005)</a> analyzed location of splice site mutations and severity of NF2, using age at onset of symptoms and number of intracranial meningiomas as indicators. They found that individuals with splice site mutations in exons 1 to 5 had more severe disease than those with splice site mutations in exons 11 to 15. <a href="#5" class="mim-tip-reference" title="Baser, M. E., Kuramoto, L., Woods, R., Joe, H., Friedman, J. M., Wallace, A. J., Ramsden, R. T., Olschwang, S., Bijlsma, E., Kalamarides, M., Papi, L., Kato, R., Carroll, J., Lazaro, C., Joncourt, F., Parry, D. M., Rouleau, G. A., Evans, D. G. R. <strong>The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2.</strong> J. Med. Genet. 42: 540-546, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15994874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15994874</a>] [<a href="https://doi.org/10.1136/jmg.2004.029504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15994874">Baser et al. (2005)</a> confirmed the previously reported observation that missense mutations are usually associated with mild NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15994874" 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>Constitutional heterozygous inactivating mutations in the NF2 gene cause the autosomal dominant disease neurofibromatosis type 2, whereas biallelic inactivating somatic NF2 mutations are found in a high proportion of unilateral sporadic vestibular schwannomas (USVSs) and sporadic meningiomas. <a href="#3" class="mim-tip-reference" title="Baser, M. E., Contributors to the International NF2 Mutation Database. <strong>The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene.</strong> Hum. Mutat. 27: 297-306, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16521120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16521120</a>] [<a href="https://doi.org/10.1002/humu.20317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16521120">Baser and Contributors to the International NF2 Mutation Database (2006)</a> surveyed the distributions of constitutional NF2 mutations in 823 NF2 families, 278 somatic NF2 mutations in USVS, and 208 somatic NF2 mutations in sporadic meningioma. Based on the available NF2 mutation data, the most dominant influence on the spectra of mutations in exon 1 through 15 were found to be C-to-T transitions that change arginine codons (CGA) to stop codons (TGA) due to spontaneous deamination of methylcytosine to thymine in CpG dinucleotides. The paucity of reported mutations in exon 9 and the absence of reported mutations in exons 16 and 17 may be related to structure-function relationships in the NF2 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16521120" 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>Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility to schwannoma. However, Nf2 hemizygous mice do not develop schwannomas but mainly osteosarcomas. In the tumors of both species, the second Nf2 allele is inactivated. <a href="#21" class="mim-tip-reference" title="Giovannini, M., Robanus-Maandag, E., van der Valk, M., Niwa-Kawakita, M., Abramowski, V., Goutebroze, L., Woodruff, J. M., Berns, A., Thomas, G. <strong>Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2.</strong> Genes Dev. 14: 1617-1630, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10887156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10887156</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10887156[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10887156">Giovannini et al. (2000)</a> reported that conditional homozygous Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann cells showed characteristics of human NF2, including schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia. Thus, the tumor suppressor function of Nf2, revealed in murine Schwann cells, was concealed in hemizygous Nf2 mice because of insufficient rate of second allele inactivation in this cell compartment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10887156" 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>After isolating a candidate gene for neurofibromatosis type 2, or vestibular shwannomatosis (SWNV; <a href="/entry/101000">101000</a>), by cloning the region of chromosome 22 between 2 flanking markers, <a href="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> succeeded in demonstrating that the gene is indeed the site of germline mutations in NF2 patients and of somatic mutations in NF2-related tumors. The search was initiated by first determining the exons and intron-exon boundaries within the coding sequence of the gene they referred to as schwannomin (SCH). Specific exons were amplified by polymerase chain reaction (PCR) and the resulting products were analyzed using denaturing gradient gel electrophoresis as described by <a href="#43" class="mim-tip-reference" title="Myers, R. M., Fischer, S. G., Lerman, L. S., Maniatis, T. <strong>Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresis.</strong> Nucleic Acids Res. 13: 3131-3145, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4000972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4000972</a>] [<a href="https://doi.org/10.1093/nar/13.9.3131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4000972">Myers et al. (1985)</a>. A total of 15 genetic variants were identified. With the exception of a leu360-to-pro mutation due to a T-to-C transition, all the variants were nonsense, frameshift, or splice mutations predicted to lead to the synthesis of a truncated SCH protein. Whenever it was possible to investigate several family members in 2 generations, the SCH mutations were found to segregate with the disease. In 3 instances, the DNA variants were present only in the patient's constitutional DNA and not in either of the unaffected parents, providing strong evidence for a causal relationship between the occurrence of a new mutation and the development of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4000972+8379998" 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=RCV000003444" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003444" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003444</a>
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<p>In a patient diagnosed with hereditary neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#47" class="mim-tip-reference" title="Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, S., Desmaze, C., Plougastel, B., Pulst, S. M., Lenoir, G., Bijlsma, E., Fashold, R., Dumanski, J., de Jong, P., Parry, D., Eldrige, R., Aurias, A., Delattre, O., Thomas, G. <strong>Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.</strong> Nature 363: 515-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8379998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8379998</a>] [<a href="https://doi.org/10.1038/363515a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8379998">Rouleau et al. (1993)</a> identified a change from AGgt to AGtt at the junction between codons 80 and 81 (presumably the splice donor site of intron 2). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8379998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MENINGIOMA, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776563;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=rs587776563" 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=rs587776563" 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=RCV000003445" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003445" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003445</a>
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<p>Among the 24 inactivating mutations in the NF2 gene found by <a href="#50" class="mim-tip-reference" title="Ruttledge, M. H., Sarrazin, J., Rangaratnam, S., Phelan, C. M., Twist, E., Merel, P., Delattre, O., Thomas, G., Nordenskjold, M., Collins, V. P., Dumanski, J. P., Rouleau, G. A. <strong>Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas.</strong> Nature Genet. 6: 180-184, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162072</a>] [<a href="https://doi.org/10.1038/ng0294-180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162072">Ruttledge et al. (1994)</a> in sporadic meningiomas (<a href="/entry/607174">607174</a>) were 7 instances of deletion of 1 bp. One of these was deletion of adenine at position 993 resulting in frameshift. An LOH pattern consistent with monosomy for chromosome 22, i.e., loss of the homologous NF2 locus, was found in this as well as in most of the other 23 tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MENINGIOMA, SOMATIC</strong>
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NF2, ARG57TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434259 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434259;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=rs121434259" 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=rs121434259" 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=RCV000003446 OR RCV000255708 OR RCV000660130 OR RCV002399307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003446, RCV000255708, RCV000660130, RCV002399307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003446...</a>
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<p><a href="#45" class="mim-tip-reference" title="Papi, L., De Vitis, L. R., Vitelli, F., Ammannati, F., Mennonna, P., Montali, E., Bigozzi, U. <strong>Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas.</strong> Hum. Genet. 95: 347-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7868131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7868131</a>] [<a href="https://doi.org/10.1007/BF00225206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7868131">Papi et al. (1995)</a> analyzed 61 sporadic meningiomas (<a href="/entry/607174">607174</a>) for loss of heterozygosity of 22q and for mutations in the NF2 gene. LOH was detected in 36 of the 60 informative tumors. They used single-strand conformation analysis to identify 9 mutations in 5 of the 8 exons of the NF2 gene studied. The 9 tumors with an altered NF2 gene also showed LOH for 22q markers, supporting the hypothesis that the NF2 gene acts as a tumor suppressor. <a href="#45" class="mim-tip-reference" title="Papi, L., De Vitis, L. R., Vitelli, F., Ammannati, F., Mennonna, P., Montali, E., Bigozzi, U. <strong>Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas.</strong> Hum. Genet. 95: 347-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7868131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7868131</a>] [<a href="https://doi.org/10.1007/BF00225206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7868131">Papi et al. (1995)</a> found no germline mutations in these cases. One of the fibroblastic meningiomas in a 62-year-old female had a C-to-T transition at codon 57 in exon 2, resulting in a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7868131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SHWANNOMATOSIS, VESTIBULAR</strong>
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NF2, LEU535PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315493 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315493;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=rs74315493" 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=rs74315493" 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=RCV000003447" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003447" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003447</a>
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<p><a href="#15" class="mim-tip-reference" title="Evans, D. G. R., Bourn, D., Wallace, A., Ramsden, R. T., Mitchell, J. D., Strachan, T. <strong>Diagnostic issues in a family with late onset type 2 neurofibromatosis.</strong> J. Med. Genet. 32: 470-474, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7666400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7666400</a>] [<a href="https://doi.org/10.1136/jmg.32.6.470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7666400">Evans et al. (1995)</a> reported a family segregating neurofibromatosis type II (NF2), or vestibular shwannomatosis (SWNV; <a href="/entry/101000">101000</a>), and late-onset tumors. Hearing loss developed late in life in 5 members of the family, 2 of whom were first shown to have NF2 in their 70s. Three other obligate gene carriers died undiagnosed at ages 64, 72, and 78 years of age. <a href="#15" class="mim-tip-reference" title="Evans, D. G. R., Bourn, D., Wallace, A., Ramsden, R. T., Mitchell, J. D., Strachan, T. <strong>Diagnostic issues in a family with late onset type 2 neurofibromatosis.</strong> J. Med. Genet. 32: 470-474, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7666400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7666400</a>] [<a href="https://doi.org/10.1136/jmg.32.6.470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7666400">Evans et al. (1995)</a> demonstrated a missense mutation at the C-terminal end of the NF2 protein; a T-to-C transition at nucleotide 1604 caused a leu535-to-pro amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7666400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4>
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<strong>.0006 SHWANNOMATOSIS, VESTIBULAR</strong>
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NF2, GLN538PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315494;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=rs74315494" 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=rs74315494" 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=RCV000003448" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003448" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003448</a>
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<p>In a family in which 4 members were diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#35" class="mim-tip-reference" title="Kluwe, L., Mautner, V.-F. <strong>A missense mutation in the NF2 gene results in moderate and mild clinical phenotypes of neurofibromatosis type 2.</strong> Hum. Genet. 97: 224-227, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566958</a>] [<a href="https://doi.org/10.1007/BF02265270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566958">Kluwe and Mautner (1996)</a> found a gln538-to-pro mutation in exon 15 of the NF2 gene by studying lymphocyte DNA. They suggested that missense mutations such as this were rare. Although both of the 2 affected members of the family who were studied developed bilateral vestibular schwannomas, the first showed onset of the disease at the age of 31 years and presented with various central, peripheral, and abdominal tumors, while the second patient showed later onset of clinical symptoms (at age 52 years) and presented with only 2 additional small spinal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8566958" 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="0007" class="mim-anchor"></a>
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<h4>
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<strong>.0007 SHWANNOMATOSIS, VESTIBULAR</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434260;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=rs121434260" 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=rs121434260" 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=RCV000003449 OR RCV002466392 OR RCV004943731" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003449, RCV002466392, RCV004943731" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003449...</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified an in-frame deletion of 3 basepairs corresponding to codon 96 (CTT) in exon 3 of the NF2 gene. The mutation causes a deletion of phenylalanine at position 96. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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">rs74315495 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315495;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=rs74315495" 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=rs74315495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a G-to-T substitution at nucleotide 544 in exon 6 of the NF2 gene, resulting in a stop codon at position 182. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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> rs74315496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315496;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/rs74315496?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=rs74315496" 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=rs74315496" 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=RCV000003451 OR RCV003231074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003451, RCV003231074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003451...</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a C-to-T substitution at nucleotide 784 in exon 8 of the NF2 gene, resulting in a stop codon at position 262. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 SHWANNOMATOSIS, VESTIBULAR</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315497 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315497;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=rs74315497" 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=rs74315497" 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">rs74315498 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315498;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=rs74315498" 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=rs74315498" 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=RCV000003452 OR RCV004018546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003452, RCV004018546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003452...</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a C-to-T substitution at nucleotide 958 in exon 10 in the NF2 gene, resulting in a stop codon at position 320. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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>.0011 SHWANNOMATOSIS, VESTIBULAR</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315499 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315499;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=rs74315499" 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=rs74315499" 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=RCV000003453 OR RCV000497720 OR RCV003278654" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003453, RCV000497720, RCV003278654" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003453...</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a C-to-T substitution at nucleotide 1021 in exon 11 of the NF2 gene, resulting in a stop codon at position 341. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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>.0012 SHWANNOMATOSIS, VESTIBULAR</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315500 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315500;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=rs74315500" 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=rs74315500" 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">rs74315501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315501;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=rs74315501" 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=rs74315501" 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=RCV000003454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003454</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a C-to-T substitution at nucleotide 1219 in exon 12 of the NF2 gene, resulting in a stop codon at position 407. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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="0013" class="mim-anchor"></a>
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<strong>.0013 SHWANNOMATOSIS, VESTIBULAR</strong>
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NF2, GLU463TER
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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> rs74315503 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315503;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/rs74315503?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=rs74315503" 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=rs74315503" 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=RCV000003455" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003455" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003455</a>
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a G-to-T substitution at nucleotide 1387 in exon 13, resulting in a stop codon at position 463. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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="0014" class="mim-anchor"></a>
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<strong>.0014 SHWANNOMATOSIS, VESTIBULAR</strong>
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NF2, ARG466TER
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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> rs74315504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315504;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/rs74315504?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=rs74315504" 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=rs74315504" 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=RCV000003456 OR RCV000992438 OR RCV002390087" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003456, RCV000992438, RCV002390087" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003456...</a>
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<p>In a study of 33 unrelated patients with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a C-to-T substitution at nucleotide 1396 in exon 13, resulting in a stop codon at position 466. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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="0015" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0015 SHWANNOMATOSIS, VESTIBULAR</strong>
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NF2, GLU527TER
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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> rs74315505 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315505;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/rs74315505?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=rs74315505" 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=rs74315505" 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=RCV000003457" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003457" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003457</a>
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</span>
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<span class="mim-text-font">
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<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>), <a href="#40" class="mim-tip-reference" title="MacCollin, M., Ramesh, V., Jacoby, L. B., Louis, D. N., Rubio, M.-P., Pulaski, K., Trofatter, J. A., Short, M. P., Bove, C., Eldridge, R., Parry, D. M., Gusella, J. F. <strong>Mutational analysis of patients with neurofibromatosis 2.</strong> Am. J. Hum. Genet. 55: 314-320, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913580</a>]" pmid="7913580">MacCollin et al. (1994)</a> identified a G-to-T substitution at nucleotide 1579 in exon 15 of the NF2 gene, resulting in a stop codon at position 527. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913580" 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="0016" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0016 SHWANNOMATOSIS, VESTIBULAR</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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<div style="float: left;">
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NF2, PHE62SER
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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">rs121434261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434261;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=rs121434261" 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=rs121434261" 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=RCV000003458 OR RCV004760318" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003458, RCV004760318" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003458...</a>
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</span>
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<p><a href="#53" class="mim-tip-reference" title="Scoles, D. R., Baser, M. E., Pulst, S.-M. <strong>A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes.</strong> Neurology 47: 544-546, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8757035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8757035</a>] [<a href="https://doi.org/10.1212/wnl.47.2.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8757035">Scoles et al. (1996)</a> found a T-to-C transition at nucleotide 185 in exon 2 of the NFw gene, resulting in a substitution of serine for phenylalanine-62, in a family with both mild and severe neurofibromatosis type II (SWNV; <a href="/entry/101000">101000</a>) phenotypes. This mutation had previously been reported by <a href="#10" class="mim-tip-reference" title="Bourn, D., Carter, S. A., Mason, S., Evans, D. G. R., Strachan, T. <strong>Germline mutations in the neurofibromatosis type 2 tumor suppressor gene.</strong> Hum. Molec. Genet. 3: 813-816, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8081368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8081368</a>] [<a href="https://doi.org/10.1093/hmg/3.5.813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8081368">Bourn et al. (1994)</a> in a family in which the phenotype of neurofibromatosis type II was uniformly mild. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8081368+8757035" 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>Paxillin (<a href="/entry/602505">602505</a>) is an adaptor protein that integrates adhesion- and growth factor-dependent signals with changes in actin organization and gene expression. Paxillin contains several protein-protein binding motifs. <a href="#18" class="mim-tip-reference" title="Fernandez-Valle, C., Tang, Y., Ricard, J., Rodenas-Ruano, A., Taylor, A., Hackler, E., Biggerstaff, J., Iacovelli, J. <strong>Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology.</strong> Nature Genet. 31: 354-362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12118253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12118253</a>] [<a href="https://doi.org/10.1038/ng930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12118253">Fernandez-Valle et al. (2002)</a> showed that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (<a href="/entry/135630">135630</a>) and ERBB2 (<a href="/entry/164870">164870</a>). The work defined a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12118253" 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="0017" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0017 SHWANNOMATOSIS, SOMATIC</strong>
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</h4>
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<span class="mim-text-font">
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NF2, 738-BP DEL
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003459</a>
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<p>In a study involving 7 patients with neurilemmomatosis (see <a href="/entry/101000">101000</a>), <a href="#27" class="mim-tip-reference" title="Honda, M., Arai, E., Sawada, S., Ohta, A., Niimura, M. <strong>Neurofibromatosis 2 and neurilemmomatosis gene are identical.</strong> J. Invest. Derm. 104: 74-77, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7798645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7798645</a>] [<a href="https://doi.org/10.1111/1523-1747.ep12613537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7798645">Honda et al. (1995)</a> analyzed peripheral leukocytes and tissue from cutaneous neurilemmomas and found a deletion from codon 334 to at least 579 in the NF2 gene. The authors considered this finding, along with that described in <a href="#0018">607379.0018</a>, sufficient to suggest that neurilemmomatosis is in fact a form of NF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7798645" 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="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 SHWANNOMATOSIS, SOMATIC</strong>
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NF2, 1-BP INS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776564;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=rs587776564" 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=rs587776564" 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=RCV000003460" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003460" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003460</a>
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<p>See <a href="#0017">607379.0017</a>. <a href="#27" class="mim-tip-reference" title="Honda, M., Arai, E., Sawada, S., Ohta, A., Niimura, M. <strong>Neurofibromatosis 2 and neurilemmomatosis gene are identical.</strong> J. Invest. Derm. 104: 74-77, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7798645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7798645</a>] [<a href="https://doi.org/10.1111/1523-1747.ep12613537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7798645">Honda et al. (1995)</a> found a G insertion at codon 42 of the NF2 gene, resulting in a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7798645" 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>.0019 SHWANNOMATOSIS, SOMATIC</strong>
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NF2, 7-BP DEL, NT105
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776565;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=rs587776565" 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=rs587776565" 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=RCV000003461" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003461" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003461</a>
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<p>In a patient with neurilemmomatosis (see <a href="/entry/101000">101000</a>), a 52-year-old man with bilateral multiple schwannomas in the legs (pain in the left leg began at the age of 45 years), <a href="#28" class="mim-tip-reference" title="Jacoby, L. B., Jones, D., Davis, K., Kronn, D., Short, M. P., Gusella, J., MacCollin, M. <strong>Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis.</strong> Am. J. Hum. Genet. 61: 1293-1302, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9399891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9399891</a>] [<a href="https://doi.org/10.1086/301633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9399891">Jacoby et al. (1997)</a> found deletion of nucleotides 205 to 211 in exon 2 of the NF2 gene. This produced a frameshift beginning at lysine-69 and leading to premature termination at codon 122. The mutation was somatic in origin inasmuch as other body cells did not show the mutation. This was despite the fact that the father and a niece were said to be affected also. Two other tumors showed different somatic mutations in NF2, a frameshift mutation in exon 5 and a frameshift mutation in exon 2. Loss of heterozygosity for markers in the region of chromosome 22 surrounding the NF2 gene was found in all 3 tumors. This and similar findings in other cases suggested to <a href="#28" class="mim-tip-reference" title="Jacoby, L. B., Jones, D., Davis, K., Kronn, D., Short, M. P., Gusella, J., MacCollin, M. <strong>Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis.</strong> Am. J. Hum. Genet. 61: 1293-1302, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9399891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9399891</a>] [<a href="https://doi.org/10.1086/301633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9399891">Jacoby et al. (1997)</a> the existence of an inherited predisposition to the formation of tumors that carry somatic alterations of the NF2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9399891" 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="Ahronowitz2007" class="mim-anchor"></a>
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Ahronowitz, I., Xin, W., Kiely, R., Sims, K., MacCollin, M., Nunes, F. P.
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<strong>Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.</strong>
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Hum. Mutat. 28: 1-12, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16983642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16983642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16983642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20393" target="_blank">Full Text</a>]
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Arai, E., Ikeuchi, T., Karasawa, S., Tamura, A., Yamamoto, K., Kida, M., Ichimura, K., Yuasa, Y., Tonomura, A.
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<strong>Constitutional translocation t(4;22)(q12;q12.2) associated with neurofibromatosis type 2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1456285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1456285</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1456285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320440209" target="_blank">Full Text</a>]
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<a id="Baser2006" class="mim-anchor"></a>
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Baser, M. E., Contributors to the International NF2 Mutation Database.
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<strong>The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene.</strong>
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Hum. Mutat. 27: 297-306, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16521120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16521120</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16521120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20317" target="_blank">Full Text</a>]
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Baser, M. E., De Rienzo, A., Altomare, D., Balsara, B. R., Hedrick, N. M., Gutmann, D. H., Pitts, L. H., Jackler, R. K., Testa, J. R.
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<strong>Neurofibromatosis 2 and malignant mesothelioma.</strong>
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Neurology 59: 290-291, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136076" 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/10.1212/wnl.59.2.290" target="_blank">Full Text</a>]
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<a id="Baser2005" class="mim-anchor"></a>
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Baser, M. E., Kuramoto, L., Woods, R., Joe, H., Friedman, J. M., Wallace, A. J., Ramsden, R. T., Olschwang, S., Bijlsma, E., Kalamarides, M., Papi, L., Kato, R., Carroll, J., Lazaro, C., Joncourt, F., Parry, D. M., Rouleau, G. A., Evans, D. G. R.
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<strong>The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2.</strong>
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J. Med. Genet. 42: 540-546, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15994874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15994874</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15994874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.029504" target="_blank">Full Text</a>]
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Bashour, A.-M., Meng, J.-J., Ip, W., MacCollin, M., Ratner, N.
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<strong>The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells.</strong>
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Molec. Cell. Biol. 22: 1150-1157, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11809806[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=11809806" 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.22.4.1150-1157.2002" target="_blank">Full Text</a>]
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<a id="Bianchi1994" class="mim-anchor"></a>
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Bianchi, A. B., Hara, T., Ramesh, V., Gao, J., Klein-Szanto, A. J. P., Morin, F., Menon, A. G., Trofatter, J. A., Gusella, J. F., Seizinger, B. R., Kley, N.
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<strong>Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types.</strong>
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Nature Genet. 6: 185-192, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162073" 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/ng0294-185" target="_blank">Full Text</a>]
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<a id="Bianchi1995" class="mim-anchor"></a>
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Bianchi, A. B., Mitsunaga, S.-I., Cheng, J. Q., Klein, W. M., Jhanwar, S. C., Seizinger, B., Kley, N., Klein-Szanto, A. J. P., Testa, J. R.
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<strong>High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas.</strong>
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Proc. Nat. Acad. Sci. 92: 10854-10858, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7479897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7479897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7479897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bijlsma, E. K., Merel, P., Bosch, D. A., Westerveld, A., Delattre, O., Thomas, G., Hulsebos, T. J. M.
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<strong>Analysis of mutations in the SCH gene in schwannomas.</strong>
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Genes Chromosomes Cancer 11: 7-14, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7529050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7529050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7529050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/gcc.2870110103" target="_blank">Full Text</a>]
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<a id="Bourn1994" class="mim-anchor"></a>
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Bourn, D., Carter, S. A., Mason, S., Evans, D. G. R., Strachan, T.
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<strong>Germline mutations in the neurofibromatosis type 2 tumor suppressor gene.</strong>
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Hum. Molec. Genet. 3: 813-816, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8081368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8081368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8081368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/3.5.813" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.8.825" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444101</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.25.3167" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="Trofatter1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munroe, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., Gusella, J. F.
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<div class="">
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1136/jmg.2003.016774" target="_blank">Full Text</a>]
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<a id="65" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<a id="66" class="mim-anchor"></a>
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<a id="Wertelecki1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wertelecki, W., Rouleau, G. A., Superneau, D. W., Forehand, L. W., Williams, J. P., Haines, J. L., Gusella, J. F.
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[<a href="https://doi.org/10.1056/NEJM198808043190505" target="_blank">Full Text</a>]
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<a id="67" class="mim-anchor"></a>
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<a id="Wolff1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wolff, R. K., Frazer, K. A., Jackler, R. K., Lanser, M. J., Pitts, L. H., Cox, D. R.
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<strong>Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1496981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1496981</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1496981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Wu2019" class="mim-anchor"></a>
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Wu, J., Minikes, A. M., Gao, M., Bian, H., Li, Y., Stockwell, B. R., Chen, Z.-N., Jiang, X.
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<strong>Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling.</strong>
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[<a href="https://doi.org/10.1038/s41586-019-1426-6" target="_blank">Full Text</a>]
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<a id="69" class="mim-anchor"></a>
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<a id="Zucman-Rossi1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zucman-Rossi, J., Legoix, P., Der Sarkissian, H., Cheret, G., Sor, F., Bernardi, A., Cazes, L., Giraud, S., Ollagnon, E., Lenoir, G., Thomas, G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/7.13.2095" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<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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Bao Lige - updated : 02/24/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/03/2019<br>Patricia A. Hartz - updated : 4/28/2011<br>Patricia A. Hartz - updated : 2/23/2009<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Victor A. McKusick - updated : 3/21/2007<br>Ada Hamosh - updated : 9/8/2006<br>Victor A. McKusick - updated : 6/6/2006<br>Marla J. F. O'Neill - updated : 9/19/2005<br>Cassandra L. Kniffin - updated : 10/21/2004<br>George E. Tiller - updated : 9/2/2004<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Victor A. McKusick - updated : 2/2/2004<br>George E. Tiller - updated : 10/13/2003<br>Victor A. McKusick - updated : 9/4/2003<br>Dawn Watkins-Chow - updated : 4/7/2003
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</span>
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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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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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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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Cassandra L. Kniffin : 11/25/2002
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/26/2023
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/29/2023<br>mgross : 02/24/2021<br>alopez : 12/03/2019<br>carol : 12/14/2017<br>alopez : 06/27/2014<br>alopez : 6/27/2014<br>tpirozzi : 10/1/2013<br>carol : 8/5/2013<br>alopez : 3/14/2013<br>alopez : 6/17/2011<br>mgross : 5/19/2011<br>terry : 4/28/2011<br>joanna : 11/23/2009<br>mgross : 2/24/2009<br>terry : 2/23/2009<br>wwang : 3/12/2008<br>ckniffin : 3/6/2008<br>alopez : 3/21/2007<br>alopez : 3/21/2007<br>alopez : 9/11/2006<br>terry : 9/8/2006<br>alopez : 6/12/2006<br>terry : 6/6/2006<br>wwang : 10/4/2005<br>terry : 9/19/2005<br>carol : 12/28/2004<br>ckniffin : 10/21/2004<br>carol : 9/3/2004<br>terry : 9/2/2004<br>carol : 8/27/2004<br>terry : 8/27/2004<br>carol : 2/12/2004<br>tkritzer : 2/3/2004<br>tkritzer : 2/2/2004<br>tkritzer : 1/23/2004<br>ckniffin : 1/21/2004<br>cwells : 10/13/2003<br>cwells : 9/8/2003<br>terry : 9/4/2003<br>cwells : 4/7/2003<br>carol : 1/29/2003<br>carol : 1/28/2003<br>ckniffin : 1/13/2003<br>ckniffin : 1/10/2003
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</span>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607379
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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NF2, MOESIN-EZRIN-RADIXIN-LIKE (MERLIN) TUMOR SUPPRESSOR; NF2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NEUROFIBROMIN 2<br />
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MERLIN<br />
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SCHWANNOMIN; SCH
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NF2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 22q12.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 22:29,603,556-29,698,600 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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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>
|
|
Inheritance
|
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</th>
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
|
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<td rowspan="3">
|
|
<span class="mim-font">
|
|
22q12.2
|
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</span>
|
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</td>
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|
|
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<td>
|
|
<span class="mim-font">
|
|
Meningioma, NF2-related, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607174
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</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">
|
|
Schwannomatosis, somatic
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
101000
|
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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">
|
|
3
|
|
</span>
|
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</td>
|
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Schwannomatosis, vestibular
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101000
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Cell-cell contact between normal cultured diploid cells results in inhibition of proliferation despite the unlimited availability of nutrients and growth-promoting factors. A similar phenomenon occurs in vivo in all adult solid tissues. NF2 is a critical regulator of contact-dependent inhibition of proliferation and functions at the interface between cell-cell adhesion, transmembrane signaling, and the actin cytoskeleton (Curto and McClatchey, 2008). </p>
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<strong>Cloning and Expression</strong>
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<p>Trofatter et al. (1993) identified a candidate gene responsible for neurofibromatosis-2 (NF2), now known as vestibular schwannomatosis or NF2-related schwannomatosis (SWNV; 101000). The authors suggested that it was a tumor suppressor gene and observed nonoverlapping deletions in DNA from 2 independent NF2 families as well as alterations in the meningiomas from 2 unrelated NF2 patients. The candidate gene encodes a deduced 595-amino acid protein with striking similarity to several members of the ERM family of proteins proposed to link cytoskeletal components with proteins in the cell membrane; these include ezrin (123900), radixin (179410), and moesin (309845). Because of the resemblance to these 3 proteins (45-47% identity), Trofatter et al. (1993) called the NF2 gene product merlin. The authors suggested that the NF2 gene may represent a novel class of tumor suppressor genes. </p><p>Rouleau et al. (1993) likewise isolated a gene, which they designated schwannomin (SCH), bearing homology to erythrocyte protein 4.1 and the ezrin/moesin/talin family of genes. To isolate the gene, they cloned the region between 2 flanking polymorphic markers in which they found several genes. One of the identified genes was the site of germline mutations in patients with neurofibromatosis-2. </p><p>By assembling overlapping cDNA fragments, Chang et al. (2002) obtained a complete NF2 cDNA. Northern blot analysis revealed a major 6.1-kb transcript expressed ubiquitously and a minor 2.7-kb transcript expressed in multiple tissues and several human cell lines. Some tissues also expressed a 3.9-kb transcript. The ratio of expression of the 6.1- and 2.7-kb transcripts was tissue specific. Chang et al. (2002) found that NF2 transcription initiates at several possible start sites and that there are 8 alternatively spliced isoforms. The predominant isoforms were designated II and I (full length and lacking exon 16, respectively). The next most frequent isoforms had deletions of exon 2, exon 3, or both. All other isoforms were expressed at low frequency. Chang et al. (2002) concluded that use of multiple polyadenylation sites likely contributes to the complexity of NF2 transcripts. </p><p>Chang et al. (2002) analyzed the promoter region of NF2. They identified a GC-rich region, but no consensus TATA sequence. Using an NF2 promoter-luciferase chimeric plasmid transfected into several cell lines, they identified a positive cis-acting element within the GC-rich sequence that could bind SP1 (189906) and GCF (189901), and they identified a negative regulatory element. By cotransfection in Drosophila cells, they confirmed that SP1 could activate the NF2 promoter through the GC-rich sequence. </p>
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<strong>Gene Structure</strong>
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<p>Rouleau et al. (1993) and Trofatter et al. (1993) determined that the NF2 gene contains 17 exons. </p>
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<strong>Mapping</strong>
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<p>The combined use of family linkage studies and tumor deletion mapping by Wertelecki et al. (1988), Rouleau et al. (1990), Wolff et al. (1992), and Arai et al. (1992) localized the NF2 gene to chromosome 22q12.2. </p><p>Claudio et al. (1994) demonstrated that the mouse homolog of the NF2 gene is located in the proximal region of chromosome 11. The localization was achieved by analysis of allele distribution in recombinant inbred strains using a simple sequence repeat polymorphism in the 3-prime untranslated region of the mouse NF2 cDNA. The region of chromosome 11 also contains genes for leukemia inhibitory factor (LIF; 159540) and neurofilament heavy chain polypeptide (NFH; 162230), both of which map to the same region of human chromosome 22 as does NF2. </p>
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<strong>Gene Function</strong>
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<p>Gutmann et al. (1999) studied rat schwannoma cell lines overexpressing wildtype merlin isoforms and mutant merlin proteins. Overexpression of wildtype merlin resulted in transient alterations in F-actin organization, cell spreading, and cell attachment, and in impaired cell motility as measured in an in vitro motility assay. These effects were observed only in cells overexpressing a merlin isoform capable of inhibiting cell growth and not with mutant merlin molecules (harboring NF2 patient mutations) or a merlin splice variant (isoform II) lacking growth-inhibitory activity. These data indicated that merlin may function to maintain normal cytoskeletal organization, and suggested that its influence on cell growth depends on specific cytoskeletal rearrangements. </p><p>Using yeast 2-hybrid and pull-down analyses, Goutebroze et al. (2000) showed that SCHIP1 (619206) interacted with schwannomin. Mutation analysis revealed that the predicted coiled-coil region of SCHIP1 was required for efficient interaction with schwannomin. Immunoprecipitation assays showed that, in vivo, SCHIP1 interacted only with some naturally occurring schwannomin mutants, or a schwannomin isoform produced from a variant lacking exons 2 and 3, but not with a schwannomin isoform exhibiting growth-suppressive activity. The authors concluded that the SCHIP1-schwannomin interaction is regulated by conformational changes in schwannomin. </p><p>Gutmann et al. (2001) performed a detailed functional analysis of 8 naturally occurring nonconservative missense mutations in the NF2 gene. The authors analyzed proliferation, actin cytoskeleton-mediated events, and merlin folding in a regulatable expression system in rat schwannoma cells. They demonstrated that mutations clustered in the predicted alpha-helical region did not impair the function of merlin, whereas those in either the N- or C-terminus of the protein rendered merlin inactive as a negative growth regulator. The authors suggested that the key functional domains of merlin may lie within the highly conserved FERM domain and the unique C terminus of the protein. </p><p>Gutmann et al. (2001) stated that the merlin protein functions as a negative growth regulator. They demonstrated that regulated overexpression of the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS, or HRS; 604375) in rat schwannoma cells yielded effects similar to those seen with overexpression of merlin, including growth inhibition, decreased motility, and abnormalities in cell spreading. The HRS binding domain of merlin was mapped to residues 453-557. Overexpression of C-terminal merlin had no effect on HRS function, suggesting to the authors that merlin binding to HRS does not negatively regulate HRS growth suppressor activity, and that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways. Gutmann (2001) reviewed the functions of neurofibromin (613113) and merlin in tumor suppression and cell-cell signaling, respectively. </p><p>Using yeast 2-hybrid interaction cloning, Scoles et al. (2000) determined that schwannomin interacts with HRS. They demonstrated the interaction both in vivo, by immunoprecipitation of endogenous HRS with endogenous schwannomin, and in vitro, with a binding assay using bacterially purified HRS and schwannomin. The regions of interaction included schwannomin residues 256-579 and HRS residues from 480 to the end of either of 2 HRS isoforms. Schwannomin molecules with an L46R, L360P, L535P, or Q538P missense mutation demonstrated reduced affinity for HRS binding. Since HRS is associated with early endosomes and may mediate receptor translocation to the lysosome, the authors used indirect immunofluorescence to demonstrate that schwannomin and HRS colocalize at endosomes in STS26T Schwann cells. The authors hypothesized that schwannomin is involved in HRS-mediated cell signaling. </p><p>Sun et al. (2002) generated a series of HRS truncation mutants to define the regions required for merlin binding and HRS growth suppression. The HRS domain required for merlin binding was narrowed to residues 470-497 (which contain the predicted coiled-coil domain), and the major domain responsible for HRS growth suppression was localized to residues 498-550. Merlin inhibited growth in Hrs +/+ but not Hrs -/- mouse embryonic fibroblast cells. In contrast, HRS could suppress cell growth in the absence of Nf2 expression. The authors concluded that merlin growth suppression requires HRS expression, and that the binding of merlin to HRS may facilitate its ability to function as a tumor suppressor. </p><p>Using transient transfection methods, Scoles et al. (2002) showed that both schwannomin and HRS inhibited STAT3 (102582) activation, and that schwannomin suppressed STAT3 activation mediated by IGF1 (147440) treatment in a human schwannoma cell line. Schwannomin inhibited STAT3 and STAT5 (601511) phosphorylation in a rat schwannoma cell line. Schwannomin with the pathogenic missense mutation Q538P (607379.0006) failed to bind HRS and did not inhibit STAT5 phosphorylation. The authors hypothesized that schwannomin requires HRS interaction to be fully functionally active and to inhibit STAT activation. </p><p>Scoles et al. (2002) noted that in addition to binding HRS, both of the major isoforms of schwannomin are involved in homodimerization and interact with beta II spectrin (182790) and with EIF3S8 (EIF3C; 603916). Homodimerization and heterodimerization between isoforms occurs through the C-terminal half, as does interaction between schwannomin and HRS and beta II spectrin. Interaction with EIF3S8 occurs through the N-terminal half of schwannomin. Using yeast 2-hybrid assays to characterize further the effect of missense mutations on these interactions, Scoles et al. (2002) found that a mutation in the N-terminal half and a mutation in the C-terminal alpha helix significantly decreased dimerization and decreased the affinity between schwannomin and all interacting proteins. Several clinically significant mutations between amino acids 219 and 352 selectively enhanced interactions with their binding partners. Scoles et al. (2002) also determined that the sites for schwannomin self-interaction and their binding strengths differ between isoforms 1 and 2. </p><p>To elucidate the properties of merlin that are critical for its tumor suppressor function, Stokowski and Cox (2000) expressed NF2-causing mutant merlin proteins in mammalian cells. They found that 80% of the merlin mutants significantly altered cell adhesion by causing cells to detach from the substratum. They stated that such changes in cell adhesion may be an initial step in the pathogenesis of NF2. In addition, they found that 4 missense mutations decreased the binding of merlin to the ERM-interacting phosphoprotein EBP-50. Some NF2 point mutations resembled dominant gain-of-function rather than loss-of-function alleles. </p><p>Fernandez-Valle et al. (2002) noted that mice with conditional deletion of NF2 exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. They found that the molecular adaptor paxillin (602505) binds directly to schwannomin in residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (ITGB1; 135630) and ERBB2 (164870). These studies defined a pathogenic mechanism for the development of neurofibromatosis-2 in humans with mutations in exon 2 of NF2. </p><p>Schulze et al. (2002) used oncoretrovirus-mediated gene transfer of different merlin constructs to stably reexpress wildtype merlin in primary cells derived from human schwannomas. Using 2-parameter FACS analysis, they demonstrated that expression of wildtype merlin in NF2 cells led to significant reduction of proliferation and G0/G1 arrest in transduced schwannoma cells. In addition, there was increased apoptosis of schwannoma cells transduced with wildtype merlin. The authors concluded that merlin may act as a tumor suppressor. </p><p>Bashour et al. (2002) observed that schwannoma-derived Schwann cells exhibited membrane ruffling and aberrant cell spreading when plated onto laminin (see 150240), indicative of fundamental F-actin cytoskeletal defects. They found that mutations in NF2 correlate with F-actin abnormalities. Using a protein transfer technique with primary human schwannoma cells containing NF2 mutations, they introduced the NF2 protein in an attempt to reverse the cytoskeletal abnormalities. They found that isoform-1 of merlin, the growth-suppressing isoform, reversed the abnormal ruffling and cell spreading and restored normal actin organization. Other isoforms of merlin and merlin containing a point mutation did not reverse the phenotype. </p><p>Gautreau et al. (2002) noted that the N-terminal FERM domain of schwannomin is implicated in plasma membrane and filamentous actin binding and that mutations in this domain impair proper folding. They found that mutations in the FERM domain were unstable both in vivo and in vitro due to proteasome-mediated degradation. They hypothesized that loss of schwannomin through degradation could contribute to the pathophysiology of NF2. </p><p>Shaw et al. (2001) concluded that NF2 functions in Rac (see 602048)-dependent signaling. Using electrophoretic mobility shift assays, they identified Rac-induced phosphorylation sites in NF2. They observed that expression of activated Rac-induced phosphorylation of the NF2 serine-518 residue inhibited NF2 self-association and decreased association of NF2 with the cytoskeleton. Using cell transfections, the authors showed that NF2 overexpression inhibited Rac-induced signaling in a phosphorylation-dependent manner. Also, NF2-deficient fibroblasts exhibited characteristics of cells overexpressing activated alleles of Rac. Shaw et al. (2001) hypothesized that NF2 functions as a tumor and metastasis suppressor through its ability to inhibit Rac-dependent signaling. </p><p>Kressel and Schmucker (2002) showed that splicing out of exon 2 leads to unrestricted entry of merlin into the nucleus, yet skipping of adjacent exon 3 has no comparable effect. Exon 2 functioned as a cytoplasmic retention factor and was able to confer sole cytoplasmic localization to a GFP fusion protein. Merlin's ability to enter the nucleus is complemented by a nuclear-cytoplasmic shuttle protein sequence within exon 15 that facilitates export via the CRM1/exportin pathway. The authors proposed a cellular function different to the wildtype protein for naturally occurring splice variants lacking exon 2. </p><p>Jin et al. (2006) identified MYPT1 (602021) as the enzyme that activates the tumor suppressor function of merlin. The cellular MYPT1-PP1-delta (600590)-specific inhibitor CPI17 (608153) caused a loss of merlin function characterized by merlin phosphorylation, Ras activation, and transformation. Constitutively active merlin containing the mutation S518A reversed CPI17-induced transformation, showing that merlin is the decisive substrate of MYPT1-PP1-delta in tumor suppression. In addition, Jin et al. (2006) showed that CPI17 levels are raised in several human tumor cell lines and that the downregulation of CPI17 induces merlin dephosphorylation, inhibits Ras activation, and abolishes the transformed phenotype. Jin et al. (2006) concluded that MYPT1 and its substrate merlin are part of a previously undescribed tumor suppressor cascade that can be hindered in 2 ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI17. </p><p>By reciprocal yeast 2-hybrid and coimmunoprecipitation analyses of the human STS26T malignant schwannoma cell line, Scoles et al. (2006) showed that isoforms 1 and 2 of schwannomin interacted with EIF3C, a subunit of eukaryotic initiation factor-3 (EIF3). Mutation analysis revealed that the FERM domain of schwannomin interacted with the C-terminal half of EIF3C. Immunofluorescence microscopy of STS26T cells showed that the 2 proteins partly colocalized at punctate perinuclear structures and at some membranous structures. Overexpression of EIF3C in STS26T cells elevated cell proliferation, and schwannomin countered this effect. Western blot analysis revealed an inverse abundance of schwannomin and EIF3C in human meningiomas. Scoles et al. (2006) concluded that schwannomin functions as a tumor suppressor by inhibiting EIF3-mediated initiation of protein translation. </p><p>Curto and McClatchey (2008) reviewed the mechanisms by which NF2 regulates contact-dependent inhibition of proliferation. </p><p>Wu et al. (2019) showed that ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin (192090) suppress ferroptosis by activating the intracellular NF2 and Hippo signaling pathway. Antagonizing this signaling axis allowed the protooncogenic transcriptional coactivator YAP (606608) to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 (300157) and TFRC (190010). This finding provided mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis. Notably, a similar mechanism also modulated ferroptosis in some nonepithelial cells. Finally, genetic inactivation of the tumor suppressor NF2, a frequent tumorigenic event in mesothelioma, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Wu et al. (2019) concluded that their results demonstrated the role of intercellular interactions and intracellular NF2-YAP signaling in dictating ferroptotic death, and also suggested that malignant mutations in NF2-YAP signaling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies. </p>
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<strong>Molecular Genetics</strong>
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<p>Rouleau et al. (1993) provided incontrovertible evidence that the NF2 gene is the site of the mutations causing neurofibromatosis-2 (NF2), now called vestibular schwannomatosis (SWNV; 101000), by demonstrating germline and somatic SCH mutations in NF2 patients and in NF2-related tumors. They found 16 mutations, 15 of which were predicted to result in truncated proteins (see 607379.0001 and 607379.0002). Consistent with the classic Knudson theory of tumor suppressor genes, loss of the wildtype allele at the NF2 locus was demonstrated in 6 of 8 tumors containing NF2 mutations (Trofatter et al., 1993; Rouleau et al., 1993). For example, in a meningioma in a patient without features of NF2, they found deletion of 2 nucleotides, TC, from codon 61 resulting in a frameshift; the normal allele on the other chromosome had been lost. In 2 instances of schwannoma occurring in patients without evidence of NF2, Rouleau et al. (1993) found nonsense mutations that were absent in the patient's blood DNA; in these instances also the normal allele had been lost. </p><p>Most of the mutations in NF2 cause the synthesis of a truncated schwannomin protein. After examining 8 of the 16 known NF2 exons in 151 meningiomas, Ruttledge et al. (1994) characterized 24 inactivating mutations. Significantly, these aberrations were detected exclusively in tumors that had lost the other chromosome 22 allele. These results provided strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene. The same group had found loss of heterozygosity (LOH) for polymorphic DNA markers flanking NF2 on chromosome 22 in 102 (60%) of 170 primary sporadic meningiomas. Thus, another gene may be involved in the development of 40% of meningiomas. All 24 of the inactivating mutations found by Ruttledge et al. (1994) in sporadic meningiomas were nonsense, frameshift (due to small deletions), or splice site mutations; there were no missense mutations. </p><p>Sainz et al. (1994) performed mutation analysis in 30 vestibular schwannomas and found 18 mutations in NF2, 7 of which contained loss or mutation of both alleles. Most mutations predicted a truncated protein. Mutation hotspots were not identified. Only 1 of the mutations was in a tumor from a patient with NF2. Immunocytochemical studies using antibodies to the NF2 protein showed complete absence of staining in tumor Schwann cells, whereas staining was observed in normal vestibular nerve. These data indicated that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene. In studies of 34 vestibular schwannomas and 14 schwannomas at other locations, Bijlsma et al. (1994) found that the SCH gene is implicated in the development of these tumors in all locations of the nervous system. </p><p>Bianchi et al. (1994) described a novel isoform of the NF2 transcript that shows differential tissue expression and encodes a modified C terminus of the predicted protein. Mutations affecting both isoforms of the NF2 transcript were detected in multiple tumor types including melanoma and breast carcinoma. These findings provided evidence that alterations in the NF2 transcript occurred not only in the hereditary brain neoplasms typically associated with NF, but also as somatic mutations in their sporadic counterparts and in seemingly unrelated tumor types. </p><p>Using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence, Merel et al. (1995) observed mutations in 17 of 57 meningiomas and in 30 of 89 schwannomas. All of the meningiomas and half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. No mutations were observed in 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. This led Merel et al. (1995) to conclude that the involvement of the NF2 gene is restricted to schwannomas and meningiomas, where it is frequently inactivated by a 2-hit process. </p><p>Wellenreuther et al. (1995) likewise concluded that NF2 represents the meningioma locus on chromosome 22. There was a significant association of loss of heterozygosity on chromosome 22 with mutations in the NF2 gene. They analyzed the entire coding region of the NF2 gene in 70 sporadic meningiomas and identified 43 mutations in 41 patients. These resulted predominantly in immediate truncation, splicing abnormalities, or an altered reading frame of the predicted protein product. All mutations occurred in the first 13 exons, the region of homology with the filopodial proteins moesin, ezrin, and radixin. </p><p>Zucman-Rossi et al. (1998) noted that although penetrance of neurofibromatosis II is greater than 95% and no genetic heterogeneity has been described, point mutations in the NF2 gene have been observed in only 34 to 66% of screened NF2 patients in various series. They deduced the entire genomic sequence of the NF2 gene and undertook a mutation screening strategy that, when applied to a series of 19 NF2 patients, revealed a high recurrence of large deletions in the gene and raised the efficiency of mutation detection in NF2 patients to 84% of the cases in this series. The remaining 3 patients who expressed 2 functional NF2 alleles were all sporadic cases, an observation compatible with the presence of mosaicism for NF2 mutations. </p><p>Legoix et al. (1999) estimated that about 50% of NF2 patients show point mutations in the NF2 gene, and that large genomic deletions account for approximately one-third of NF2 gene alterations. To facilitate deletion screening, they identified 16 polymorphic markers in the NF2 genomic sequence, enabling a hemizygosity test in familial studies. </p><p>Kluwe et al. (2000) studied 40 skin tumors (36 schwannomas and 4 neurofibromas) from 20 NF2 patients, 15 of whom had NF2 mutations previously identified in blood leukocytes. The detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%). They found NF2 mutations in 5 tumors (13%) and NF2 allelic loss in 18 (45%) of the 40 examined tumors. Alterations in both NF2 alleles were found in 17 (43%) of the tumors. They concluded that loss of a functional NF2 gene product is a critical event in the generation of skin schwannomas and that mutation detection in skin tumors may be a useful diagnostic tool in patients with skin tumors where the clinical diagnosis of NF2 is ambiguous, or in unclear cases in which NF1 must be excluded. </p><p>Tsilchorozidou et al. (2004) reported 5 NF2 patients with constitutional rearrangements of chromosome 22 and vestibular schwannomas, multiple intracranial meningiomas, and spinal tumors. The authors noted that an additional 10 NF2 patients with constitutional NF2 deletions had been discovered using NF2 FISH in their laboratory, and suggested that chromosome analysis with FISH might be a useful first screen prior to molecular testing in NF2 patients. </p><p>Kluwe et al. (2000) studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In 45 informative individuals, 31 mutations (69%) were of paternal origin and 14 (31%) of maternal origin. In 4 of 6 patients with somatic mosaicism, the NF2 mutation was of maternal origin. </p><p>Ahronowitz et al. (2007) presented a metaanalysis of 967 constitutional and somatic NF2 alterations from 93 published reports, along with 59 additional unpublished mutations identified in their laboratory and 115 alterations identified in clinical samples submitted to the Neurogenetics DNA Diagnostic Laboratory of the Massachusetts General Hospital. In total, these sources defined 1,070 small genetic changes detected primarily by exon scanning, 42 intragenic changes of 1 whole exon or larger, and 29 whole gene deletions and gross chromosomal rearrangements. Overall, somatic events showed a significantly different genetic profile than constitutional events. Somatic events were strongly skewed toward frameshift (accounting for over one-half of these mutations) in comparison to constitutional changes that were primarily nonsense and splice site, as had been previously described by Baser and Contributors to the International NF2 Mutation Database (2006). Somatic events also differed markedly between tumors of different pathology, most significantly in the tendency of somatic events in meningiomas to lie within the 5-prime FERM domain of the transcript with a complete absence of mutations in exons 14 and 15. Less than 10% of all published and unpublished small alterations were nontruncating and these changes were clustered in exons 2 and 3, suggesting that this region may be especially crucial to tumor suppressor activity in the protein. </p><p><strong><em>Somatic Mosaicism</em></strong></p><p>
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Evans et al. (1998) sought mutations in the NF2 gene in 125 families with classic NF2 with bilateral vestibular schwannomas; causative mutations were identified in 52 families. In 5 families, the first affected individual in the family was a mosaic for a disease-causing mutation. Only 1 of the 9 children from the 3 mosaic cases with children were affected. Four of these 9 children inherited the allele associated with the disease-causing mutation yet did not inherit the mutation. NF2 mutations were identified in only 27 of 79 (34%) sporadic cases, compared with 25 of 46 (54%) familial cases (P less than 0.05). In 48 families in which a mutation had not been identified, the index cases had 125 children, of whom only 29 were affected with NF2 and of whom only a further 21 cases would be predicted to be affected by use of life curves. The 50 of 125 (40%) cases is significantly less than the 50% expected eventually to develop NF2 (P less than 0.05). Somatic mosaicism is likely to be a common cause of classic NF2 and may well account for a low detection rate for mutations in sporadic cases. Degrees of gonosomal mosaicism mean that recurrence risks may well be less than 50% in the offspring of the index case when a mutation was not identified in lymphocyte DNA. </p><p>Kluwe and Mautner (1998) concluded that mosaicism is relatively common in NF2, with important implications for diagnosis, prognosis, and genetic counseling. In 4 sporadic NF2 patients, they found NF2 mutations in only a portion of leukocytes. In 2 other sporadic patients, no mutations were found in leukocytes but constitutional NF2 mutations were suggested by the finding of identical mutations in different tumors from each patient. Kluwe and Mautner (1998) screened leukocyte DNA from a total of 16 inherited and 91 sporadic NF2 patients, and found NF2 mutations in 13 (81%) of the former and in 46 (51%) of the latter cases. They suspected that the 30% difference in the rate of detection of mutations might be partially explained by mosaicism in a portion of sporadic NF2 patients who carry the mutations in such a fashion that their leukocytes are unaffected. Among sporadic cases, they found mutations to be more frequent in patients with severe phenotypes (59%) than in patients with mild phenotypes (23%). This likewise might be explained by mosaicism, with the smaller population of mutation-bearing cells resulting in mild phenotypes. No mutations were found in 8 patients suspected of having NF2. </p><p>Sestini et al. (2000) reported the genetic study of 33 NF2 patients from 33 unrelated Italian families. Twelve mutations were characterized, including 7 newly identified mutations and 5 recurrent ones. Furthermore, they described 1 patient with an inactivating mutation in exon 13 present in only a portion of the lymphocytes and, more importantly, a clinically normal individual carrying a somatic/germinal mosaicism for a nonsense mutation in exon 10 of the NF2 gene. The results confirmed the relatively high percentage of mosaicism for mutations in the NF2 gene and established the importance of evaluating genomic DNA from several tissues, in addition to lymphocytes, so as to identify mosaicism in 'de novo' NF2 patients and their relatives. </p><p>Moyhuddin et al. (2003) described mutation analysis of 27 mosaic cases of NF2 and the results of genetic testing in their children. They estimated that 30% of de novo NF2 patients are mosaic. The authors suggested that mosaicism should be suspected in a mildly affected isolated patient with no mutation detected in blood. Risk of transmission to offspring is small in an NF2 patient with a mutation detectable only in tumor. </p><p>Kluwe et al. (2003) identified mutations in the NF2 gene in peripheral blood of 122 of 233 (52%) NF2 founders (those with clinically unaffected parents). Mutations in the NF2 gene were identified in 21 of 35 available tumor specimens from the 111 patients who did not have detectable peripheral blood mutations. Nine of these patients had a constitutional mutation which was also found in distinct second tumors. Kluwe et al. (2003) concluded that failure to find NF2 mutations in peripheral blood of NF2 mutations was due to somatic mosaicism. By extrapolation, the authors estimated that the rate of somatic mosaicism in their cohort was 24.8%. </p><p><strong><em>Schwannomatosis</em></strong></p><p>
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Neurilemmomatosis (162091), also called schwannomatosis, first reported by Niimura (1973) as neurofibromatosis type 3, is characterized by multiple cutaneous neurilemmomas and spinal schwannomas, without acoustic tumors or other signs of NF1 or NF2. In neurilemmomas, the tumor consists of Schwann cells. Honda et al. (1995) analyzed the peripheral leukocytes and tissue from cutaneous neurilemmomas of 7 patients with neurilemmomatosis using DNA markers for different regions of chromosome 22. They detected allele losses in 3 of 7 tumors from 7 patients with a probe for the NF2 region and the germline mutations in 2 of 3 tumors from the same 3 patients. They described 2 mutations in the NF2 gene (607379.0017; 607379.0018). They concluded that neurilemmomatosis is a form of NF2. </p><p>Jacoby et al. (1997) investigated the molecular genetic basis of schwannomatosis in patients with multiple schwannomas without vestibular schwannomas, which has been postulated to represent a distinct subclass of neurofibromatosis. They found the unusual situation that in studies of 20 unrelated schwannomatosis patients and their affected relatives, tumors from the patients frequently harbored typical truncating mutations of the NF2 gene and loss of heterozygosity of the surrounding region of chromosome 22. Surprisingly, unlike patients with NF2, no heterozygous NF2 gene changes were seen in normal tissues. Furthermore, examination of multiple tumors from the same patients revealed that some schwannomatosis patients are somatic mosaics for NF2 gene changes. By contrast, other individuals, particularly those with a positive family history, appeared to have an inherited predisposition to formation of tumors that carry somatic alterations of the NF2 gene. </p><p>In 7 tumor specimens resected from a 36-year-old man with schwannomatosis, Kaufman et al. (2003) found LOH at the NF2 locus in all tumors, and in every case the same allele was lost, implying that somatic mutations accumulate on the same retained allele. Four of the specimens contained unrelated truncating mutations of the NF2 gene. </p><p>Sestini et al. (2008) identified somatic mutations in the NF2 gene in tumor tissue derived from 3 unrelated patients with schwannomatosis. LOH was also observed in all cases. </p><p><strong><em>Malignant Mesothelioma</em></strong></p><p>
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Malignant mesotheliomas (MMs; 156240) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations had been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. This prompted Bianchi et al. (1995) to investigate the status of the NF2 gene in these tumors. In studies of cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors, NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in 8 cell lines (53%), 6 of which were confirmed in primary tumor DNAs. In 2 samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. Unlike previously described NF2-related tumors, MM derived from the mesoderm; malignancies of this origin had not previously been associated with frequent alterations of the NF2 gene. In a commentary in the same journal issue, Knudson (1995) wrote: 'We are left wondering why mesothelioma is not a feature of the hereditary disease NF2.' Baser et al. (2002) reported a patient with NF2 who developed malignant mesothelioma after a long occupational exposure to asbestos. Genetic analysis of the tumor tissue showed loss not only of chromosome 22 but also of chromosomes 14 and 15, and gain of chromosome 7. Baser et al. (2002) suggested that an individual with a constitutional mutation of an NF2 allele, as in NF2, is more susceptible to mesothelioma. Although mesothelioma is not a common feature in NF2, the authors cited the observation of Knudson (1995) that somatic mutations of a tumor suppressor gene, such as NF2, RB1 (614041), or p53 (191170), can be common in a tumor type that is not characteristic of the hereditary disorder, perhaps due to the proliferative timing of the cells involved. </p><p>Fleury-Feith et al. (2003) noted that biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. To assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibers, they investigated the NF2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene, after intraperitoneal inoculation of crocidolite fibers. Asbestos-exposed mice heterozygous for a knockout of Nf2 developed tumoral ascites and mesothelioma at higher frequency than their wildtype counterparts (P less than 0.05). Six out of 7 mesothelioma cell lines established from neoplastic ascitic fluids of these heterozygous knockout mice exhibited loss of the wildtype Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results showed the importance of the Nf2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumor suppressor gene inactivation, and suggested that NF2 gene mutation may be a susceptibility factor to asbestos. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Parry et al. (1996) used SSCP analysis to screen for mutations in DNA from 32 unrelated NF2 patients. Mutations were identified in 66% of patients and 20 different mutations were found in 21 patients. They suggested that their results confirmed the association between nonsense and frameshift mutations and clinical manifestations compatible with severe disease. They stated that their data raised questions regarding the role of other factors, in addition to the intrinsic properties of individual mutations, that might influence the phenotype. Ruttledge et al. (1996) reported that when individuals harboring protein-truncating mutations are compared with patients having single codon alterations, a significant correlation (p less than 0.001) with clinical outcome is observed. They noted that 24 of 28 patients with mutations that cause premature termination of the NF2 protein presented with severe phenotypes. In contrast, all 16 cases from 3 families with mutations that affect only a single amino acid had mild NF2. </p><p>Evans et al. (1998) reported 42 cases of NF2 from 38 families with truncating mutations. The average age of onset of symptoms was 19 years and age at diagnosis 22.4 years. Fifty-one cases from 16 families (15 with splice site mutations, 18 with missense mutations, and 18 with large deletions) had an average age of onset of 27.8 years and age at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to develop symptoms before 20 years of age (p less than 0.001) and to develop at least 2 symptomatic CNS tumors in addition to vestibular schwannoma before 30 years (p less than 0.001). There were significantly fewer multigenerational families with truncating mutations. </p><p>Kehrer-Sawatzki et al. (1997) reported a patient with NF2 and a ring chromosome 22 (46,XX,r(22)/45,XX,-22). Severe manifestations included multiple meningiomas, spinal and peripheral neurinomas, and bilateral vestibular schwannomas. The patient was also severely mentally retarded, a feature not usually associated with NF2. The authors hypothesized that a mutation in the NF2 gene of the normal chromosome 22, in addition to the loss of the ring 22 in many cells during mitosis, could explain the presence of multiple tumors. Using a meningioma cell line lacking the ring chromosome, Kehrer-Sawatzki et al. (1997) searched for deletions, rearrangements, or other mutations of the NF2 gene on the normal chromosome 22; no such alterations were found. The authors concluded that the loss of the entire chromosome 22 and its multiple tumor suppressor genes may have led to the severe phenotype in this patient. </p><p>Bruder et al. (2001) examined the 7-Mb interval in the vicinity of the NF2 gene in a series of 116 NF2 patients in order to determine the frequency and extent of deletions. Using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of the region around the NF2 locus, deletions of various sizes were detected in 8 severe, 10 moderate, and 6 mild patients. This result did not support a correlation between the type of mutation affecting the NF2 gene and the disease phenotype. </p><p>In 831 patients from 528 NF2 families, Baser et al. (2005) analyzed location of splice site mutations and severity of NF2, using age at onset of symptoms and number of intracranial meningiomas as indicators. They found that individuals with splice site mutations in exons 1 to 5 had more severe disease than those with splice site mutations in exons 11 to 15. Baser et al. (2005) confirmed the previously reported observation that missense mutations are usually associated with mild NF2. </p><p>Constitutional heterozygous inactivating mutations in the NF2 gene cause the autosomal dominant disease neurofibromatosis type 2, whereas biallelic inactivating somatic NF2 mutations are found in a high proportion of unilateral sporadic vestibular schwannomas (USVSs) and sporadic meningiomas. Baser and Contributors to the International NF2 Mutation Database (2006) surveyed the distributions of constitutional NF2 mutations in 823 NF2 families, 278 somatic NF2 mutations in USVS, and 208 somatic NF2 mutations in sporadic meningioma. Based on the available NF2 mutation data, the most dominant influence on the spectra of mutations in exon 1 through 15 were found to be C-to-T transitions that change arginine codons (CGA) to stop codons (TGA) due to spontaneous deamination of methylcytosine to thymine in CpG dinucleotides. The paucity of reported mutations in exon 9 and the absence of reported mutations in exons 16 and 17 may be related to structure-function relationships in the NF2 protein. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility to schwannoma. However, Nf2 hemizygous mice do not develop schwannomas but mainly osteosarcomas. In the tumors of both species, the second Nf2 allele is inactivated. Giovannini et al. (2000) reported that conditional homozygous Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann cells showed characteristics of human NF2, including schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia. Thus, the tumor suppressor function of Nf2, revealed in murine Schwann cells, was concealed in hemizygous Nf2 mice because of insufficient rate of second allele inactivation in this cell compartment. </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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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 SHWANNOMATOSIS, VESTIBULAR</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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NF2, LEU360PRO
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<br />
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SNP: rs74315492,
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ClinVar: RCV000003443
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</span>
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<div>
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<span class="mim-text-font">
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<p>After isolating a candidate gene for neurofibromatosis type 2, or vestibular shwannomatosis (SWNV; 101000), by cloning the region of chromosome 22 between 2 flanking markers, Rouleau et al. (1993) succeeded in demonstrating that the gene is indeed the site of germline mutations in NF2 patients and of somatic mutations in NF2-related tumors. The search was initiated by first determining the exons and intron-exon boundaries within the coding sequence of the gene they referred to as schwannomin (SCH). Specific exons were amplified by polymerase chain reaction (PCR) and the resulting products were analyzed using denaturing gradient gel electrophoresis as described by Myers et al. (1985). A total of 15 genetic variants were identified. With the exception of a leu360-to-pro mutation due to a T-to-C transition, all the variants were nonsense, frameshift, or splice mutations predicted to lead to the synthesis of a truncated SCH protein. Whenever it was possible to investigate several family members in 2 generations, the SCH mutations were found to segregate with the disease. In 3 instances, the DNA variants were present only in the patient's constitutional DNA and not in either of the unaffected parents, providing strong evidence for a causal relationship between the occurrence of a new mutation and the development of the disease. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SHWANNOMATOSIS, VESTIBULAR</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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NF2, IVS2, G-T, +1
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<br />
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SNP: rs587776562,
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ClinVar: RCV000003444
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient diagnosed with hereditary neurofibromatosis type II (SWNV; 101000), Rouleau et al. (1993) identified a change from AGgt to AGtt at the junction between codons 80 and 81 (presumably the splice donor site of intron 2). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MENINGIOMA, SOMATIC</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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NF2, 1-BP DEL, 993A
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<br />
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SNP: rs587776563,
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ClinVar: RCV000003445
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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>Among the 24 inactivating mutations in the NF2 gene found by Ruttledge et al. (1994) in sporadic meningiomas (607174) were 7 instances of deletion of 1 bp. One of these was deletion of adenine at position 993 resulting in frameshift. An LOH pattern consistent with monosomy for chromosome 22, i.e., loss of the homologous NF2 locus, was found in this as well as in most of the other 23 tumors. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MENINGIOMA, SOMATIC</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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NF2, ARG57TER
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<br />
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SNP: rs121434259,
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ClinVar: RCV000003446, RCV000255708, RCV000660130, RCV002399307
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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>Papi et al. (1995) analyzed 61 sporadic meningiomas (607174) for loss of heterozygosity of 22q and for mutations in the NF2 gene. LOH was detected in 36 of the 60 informative tumors. They used single-strand conformation analysis to identify 9 mutations in 5 of the 8 exons of the NF2 gene studied. The 9 tumors with an altered NF2 gene also showed LOH for 22q markers, supporting the hypothesis that the NF2 gene acts as a tumor suppressor. Papi et al. (1995) found no germline mutations in these cases. One of the fibroblastic meningiomas in a 62-year-old female had a C-to-T transition at codon 57 in exon 2, resulting in a premature stop codon. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SHWANNOMATOSIS, VESTIBULAR</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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NF2, LEU535PRO
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<br />
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SNP: rs74315493,
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ClinVar: RCV000003447
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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>Evans et al. (1995) reported a family segregating neurofibromatosis type II (NF2), or vestibular shwannomatosis (SWNV; 101000), and late-onset tumors. Hearing loss developed late in life in 5 members of the family, 2 of whom were first shown to have NF2 in their 70s. Three other obligate gene carriers died undiagnosed at ages 64, 72, and 78 years of age. Evans et al. (1995) demonstrated a missense mutation at the C-terminal end of the NF2 protein; a T-to-C transition at nucleotide 1604 caused a leu535-to-pro 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">
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<strong>.0006 SHWANNOMATOSIS, VESTIBULAR</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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NF2, GLN538PRO
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<br />
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SNP: rs74315494,
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ClinVar: RCV000003448
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family in which 4 members were diagnosed with neurofibromatosis type II (SWNV; 101000), Kluwe and Mautner (1996) found a gln538-to-pro mutation in exon 15 of the NF2 gene by studying lymphocyte DNA. They suggested that missense mutations such as this were rare. Although both of the 2 affected members of the family who were studied developed bilateral vestibular schwannomas, the first showed onset of the disease at the age of 31 years and presented with various central, peripheral, and abdominal tumors, while the second patient showed later onset of clinical symptoms (at age 52 years) and presented with only 2 additional small spinal tumors. </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 SHWANNOMATOSIS, VESTIBULAR</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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NF2, PHE96DEL
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<br />
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SNP: rs121434260,
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ClinVar: RCV000003449, RCV002466392, RCV004943731
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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 study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified an in-frame deletion of 3 basepairs corresponding to codon 96 (CTT) in exon 3 of the NF2 gene. The mutation causes a deletion of phenylalanine at position 96. </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>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, GLU182TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315495,
|
|
|
|
|
|
|
|
ClinVar: RCV000003450
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a G-to-T substitution at nucleotide 544 in exon 6 of the NF2 gene, resulting in a stop codon at position 182. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, ARG262TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315496,
|
|
|
|
|
|
gnomAD: rs74315496,
|
|
|
|
|
|
ClinVar: RCV000003451, RCV003231074
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a C-to-T substitution at nucleotide 784 in exon 8 of the NF2 gene, resulting in a stop codon at position 262. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, GLN320TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315497, rs74315498,
|
|
|
|
|
|
|
|
ClinVar: RCV000003452, RCV004018546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a C-to-T substitution at nucleotide 958 in exon 10 in the NF2 gene, resulting in a stop codon at position 320. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, ARG341TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315499,
|
|
|
|
|
|
|
|
ClinVar: RCV000003453, RCV000497720, RCV003278654
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a C-to-T substitution at nucleotide 1021 in exon 11 of the NF2 gene, resulting in a stop codon at position 341. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, GLN407TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315500, rs74315501,
|
|
|
|
|
|
|
|
ClinVar: RCV000003454
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a C-to-T substitution at nucleotide 1219 in exon 12 of the NF2 gene, resulting in a stop codon at position 407. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, GLU463TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315503,
|
|
|
|
|
|
gnomAD: rs74315503,
|
|
|
|
|
|
ClinVar: RCV000003455
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a G-to-T substitution at nucleotide 1387 in exon 13, resulting in a stop codon at position 463. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, ARG466TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315504,
|
|
|
|
|
|
gnomAD: rs74315504,
|
|
|
|
|
|
ClinVar: RCV000003456, RCV000992438, RCV002390087
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a C-to-T substitution at nucleotide 1396 in exon 13, resulting in a stop codon at position 466. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, GLU527TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315505,
|
|
|
|
|
|
gnomAD: rs74315505,
|
|
|
|
|
|
ClinVar: RCV000003457
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 33 unrelated patients diagnosed with neurofibromatosis type II (SWNV; 101000), MacCollin et al. (1994) identified a G-to-T substitution at nucleotide 1579 in exon 15 of the NF2 gene, resulting in a stop codon at position 527. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 SHWANNOMATOSIS, VESTIBULAR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, PHE62SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434261,
|
|
|
|
|
|
|
|
ClinVar: RCV000003458, RCV004760318
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Scoles et al. (1996) found a T-to-C transition at nucleotide 185 in exon 2 of the NFw gene, resulting in a substitution of serine for phenylalanine-62, in a family with both mild and severe neurofibromatosis type II (SWNV; 101000) phenotypes. This mutation had previously been reported by Bourn et al. (1994) in a family in which the phenotype of neurofibromatosis type II was uniformly mild. </p><p>Paxillin (602505) is an adaptor protein that integrates adhesion- and growth factor-dependent signals with changes in actin organization and gene expression. Paxillin contains several protein-protein binding motifs. Fernandez-Valle et al. (2002) showed that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (135630) and ERBB2 (164870). The work defined a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 SHWANNOMATOSIS, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, 738-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003459
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study involving 7 patients with neurilemmomatosis (see 101000), Honda et al. (1995) analyzed peripheral leukocytes and tissue from cutaneous neurilemmomas and found a deletion from codon 334 to at least 579 in the NF2 gene. The authors considered this finding, along with that described in 607379.0018, sufficient to suggest that neurilemmomatosis is in fact a form of NF2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 SHWANNOMATOSIS, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, 1-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776564,
|
|
|
|
|
|
|
|
ClinVar: RCV000003460
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 607379.0017. Honda et al. (1995) found a G insertion at codon 42 of the NF2 gene, resulting in a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 SHWANNOMATOSIS, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF2, 7-BP DEL, NT105
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776565,
|
|
|
|
|
|
|
|
ClinVar: RCV000003461
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurilemmomatosis (see 101000), a 52-year-old man with bilateral multiple schwannomas in the legs (pain in the left leg began at the age of 45 years), Jacoby et al. (1997) found deletion of nucleotides 205 to 211 in exon 2 of the NF2 gene. This produced a frameshift beginning at lysine-69 and leading to premature termination at codon 122. The mutation was somatic in origin inasmuch as other body cells did not show the mutation. This was despite the fact that the father and a niece were said to be affected also. Two other tumors showed different somatic mutations in NF2, a frameshift mutation in exon 5 and a frameshift mutation in exon 2. Loss of heterozygosity for markers in the region of chromosome 22 surrounding the NF2 gene was found in all 3 tumors. This and similar findings in other cases suggested to Jacoby et al. (1997) the existence of an inherited predisposition to the formation of tumors that carry somatic alterations of the NF2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ahronowitz, I., Xin, W., Kiely, R., Sims, K., MacCollin, M., Nunes, F. P.
|
|
<strong>Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.</strong>
|
|
Hum. Mutat. 28: 1-12, 2007.
|
|
|
|
|
|
[PubMed: 16983642]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.20393]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arai, E., Ikeuchi, T., Karasawa, S., Tamura, A., Yamamoto, K., Kida, M., Ichimura, K., Yuasa, Y., Tonomura, A.
|
|
<strong>Constitutional translocation t(4;22)(q12;q12.2) associated with neurofibromatosis type 2.</strong>
|
|
Am. J. Med. Genet. 44: 163-167, 1992.
|
|
|
|
|
|
[PubMed: 1456285]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1320440209]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baser, M. E., Contributors to the International NF2 Mutation Database.
|
|
<strong>The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene.</strong>
|
|
Hum. Mutat. 27: 297-306, 2006.
|
|
|
|
|
|
[PubMed: 16521120]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.20317]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baser, M. E., De Rienzo, A., Altomare, D., Balsara, B. R., Hedrick, N. M., Gutmann, D. H., Pitts, L. H., Jackler, R. K., Testa, J. R.
|
|
<strong>Neurofibromatosis 2 and malignant mesothelioma.</strong>
|
|
Neurology 59: 290-291, 2002.
|
|
|
|
|
|
[PubMed: 12136076]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.59.2.290]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baser, M. E., Kuramoto, L., Woods, R., Joe, H., Friedman, J. M., Wallace, A. J., Ramsden, R. T., Olschwang, S., Bijlsma, E., Kalamarides, M., Papi, L., Kato, R., Carroll, J., Lazaro, C., Joncourt, F., Parry, D. M., Rouleau, G. A., Evans, D. G. R.
|
|
<strong>The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2.</strong>
|
|
J. Med. Genet. 42: 540-546, 2005.
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Bao Lige - updated : 02/24/2021<br>Ada Hamosh - updated : 12/03/2019<br>Patricia A. Hartz - updated : 4/28/2011<br>Patricia A. Hartz - updated : 2/23/2009<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Victor A. McKusick - updated : 3/21/2007<br>Ada Hamosh - updated : 9/8/2006<br>Victor A. McKusick - updated : 6/6/2006<br>Marla J. F. O'Neill - updated : 9/19/2005<br>Cassandra L. Kniffin - updated : 10/21/2004<br>George E. Tiller - updated : 9/2/2004<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Victor A. McKusick - updated : 2/2/2004<br>George E. Tiller - updated : 10/13/2003<br>Victor A. McKusick - updated : 9/4/2003<br>Dawn Watkins-Chow - updated : 4/7/2003
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