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Entry
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- *611223 - AKT SERINE/THREONINE KINASE 3; AKT3
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- OMIM
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<p>
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<span class="h4">*611223</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#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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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/611223">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div 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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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000117020;t=ENST00000673466" 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=10000" 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=611223" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000117020;t=ENST00000673466" 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_001206729,NM_001370074,NM_005465,NM_181690,XM_011544014,XM_024446892,XM_024447938,XM_047415643,XM_047417359,XM_047419186,XM_047420641,XM_047422391,XM_047424332" 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_005465" 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=611223" 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="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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<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=06441&isoform_id=06441_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/AKT3" 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/4574744,4757579,4885549,5804886,5912043,12309761,12643943,15072340,15985014,17529663,32307163,62089468,111305899,119597499,119597500,332078559,767912019,1370451447,1370451449,1624702966,2217262923,2217262925,2217262927,2217262929,2217262931,2217262933,2462489251,2462489253,2462489255,2462489257,2462489259,2462489261,2462489263,2462489265,2462501846,2462501848,2462501850,2462501852,2462501854,2462501856,2462501858,2462501860" 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/Q9Y243" 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 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=10000" 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=ENSG00000117020;t=ENST00000673466" 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=AKT3" 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=AKT3" 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+10000" 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/AKT3" 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:10000" 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/10000" 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=chr1&hgg_gene=ENST00000673466.1&hgg_start=243488233&hgg_end=243851079&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:393" 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:393" 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/akt3" 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=611223[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=611223[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/AKT3/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/ENSG00000117020" 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=AKT3" 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=AKT3" 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=AKT3" 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=AKT3&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/PA24686" 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:393" 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/FBgn0010379.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:1345147" 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/AKT3#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:1345147" 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/10000/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=10000" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
|
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<div id="mimWormbaseGeneFold" class="collapse">
|
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000102;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000102 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000103;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000103 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-050419-180" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10000" 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=AKT3&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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611223
|
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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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AKT SERINE/THREONINE KINASE 3; AKT3
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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>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 3<br />
|
|
PROTEIN KINASE B, GAMMA; PKBG<br />
|
|
PKB-GAMMA
|
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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>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
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MAGI3/AKT3 FUSION GENE, INCLUDED
|
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</span>
|
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</div>
|
|
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=AKT3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AKT3</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1845?start=-3&limit=10&highlight=1845">1q43-q44</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:243488233-243851079&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'})">1:243,488,233-243,851,079</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1845?start=-3&limit=10&highlight=1845">
|
|
1q43-q44
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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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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<p>Members of the AKT protein family, such as AKT3, are implicated in numerous biologic processes, including adipocyte and muscle differentiation, glycogen synthesis, glucose uptake, apoptosis, and cellular proliferation (<a href="#10" class="mim-tip-reference" title="Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A. <strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong> Biochem. Biophys. Res. Commun. 257: 906-910, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208883</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208883">Nakatani et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using mouse Pkb-gamma to screen several human cDNA libraries, followed by 5-prime RACE of a human brain cDNA library, <a href="#3" class="mim-tip-reference" title="Brodbeck, D., Cron, P., Hemmings, B. A. <strong>A human protein kinase B-gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain.</strong> J. Biol. Chem. 274: 9133-9136, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10092583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10092583</a>] [<a href="https://doi.org/10.1074/jbc.274.14.9133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10092583">Brodbeck et al. (1999)</a> cloned AKT3, which they called PKB-gamma. The deduced 479-amino acid protein contains a pleckstrin (<a href="/entry/173570">173570</a>) homology (PH) domain, an activation loop, and a C-terminal hydrophobic domain. PKB-gamma shares 83% and 78% amino acid identity with human PKB-alpha (AKT1; <a href="/entry/164730">164730</a>) and PKB-beta (AKT2; <a href="/entry/164731">164731</a>), respectively, and more than 99% identity with mouse Pkb-gamma. Northern blot analysis detected transcripts of 6.5 and 8.5 kb in all adult tissues examined, with highest expression in brain, lung, and kidney and lowest expression in heart and liver. Transcripts of the same size were detected in all fetal tissues examined except kidney, with highest expression in heart, brain, and liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10092583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Independently, <a href="#10" class="mim-tip-reference" title="Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A. <strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong> Biochem. Biophys. Res. Commun. 257: 906-910, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208883</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208883">Nakatani et al. (1999)</a> cloned AKT3. Northern blot analysis detected highest expression of 5.3- and 7.7-kb transcripts in brain, heart, and placenta, with weaker expression in skeletal muscle, kidney, and pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A. <strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong> Biochem. Biophys. Res. Commun. 257: 906-910, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208883</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208883">Nakatani et al. (1999)</a> determined that the AKT3 gene contains 2 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using FISH, <a href="#8" class="mim-tip-reference" title="Murthy, S. S., Tosolini, A., Taguchi, T., Testa, J. R. <strong>Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 88: 38-40, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10773662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10773662</a>] [<a href="https://doi.org/10.1159/000015481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10773662">Murthy et al. (2000)</a> mapped the AKT3 gene to chromosome 1q44. They mapped the mouse Akt3 gene to chromosome 1H4-H6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10773662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Deletions of 1q42-q44 (<a href="/entry/612337">612337</a>) have been reported in a variety of developmental abnormalities of brain, including microcephaly and agenesis of the corpus callosum. <a href="#2" class="mim-tip-reference" title="Boland, E., Clayton-Smith, J., Woo, V. G., McKee, S., Manson, F. D. C., Medne, L., Zackai, E., Swanson, E. A., Fitzpatrick, D., Millen, K. J., Sherr, E. H., Dobyns, W. B., Black, G. C. M. <strong>Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.</strong> Am. J. Hum. Genet. 81: 292-303, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668379[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/10.1086/519999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17668379">Boland et al. (2007)</a> described detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These defined a 3.5-Mb critical region that was hypothesized to contain 1 or more genes that lead to agenesis of the corpus callosum and microcephaly when present in only 1 functional copy. Mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal microcephaly and agenesis of the corpus callosum demonstrated a breakpoint in this region that was situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine ortholog Akt3 is required for developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with agenesis of the corpus callosum did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of AKT3 in the developing central nervous system during mouse embryogenesis. <a href="#2" class="mim-tip-reference" title="Boland, E., Clayton-Smith, J., Woo, V. G., McKee, S., Manson, F. D. C., Medne, L., Zackai, E., Swanson, E. A., Fitzpatrick, D., Millen, K. J., Sherr, E. H., Dobyns, W. B., Black, G. C. M. <strong>Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.</strong> Am. J. Hum. Genet. 81: 292-303, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668379[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/10.1086/519999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17668379">Boland et al. (2007)</a> concluded that thus, AKT3 represents an excellent candidate for developmental human microcephaly and agenesis of the corpus callosum, and suggested that haploinsufficiency causes postnatal microcephaly and agenesis of the corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17668379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Brodbeck, D., Cron, P., Hemmings, B. A. <strong>A human protein kinase B-gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain.</strong> J. Biol. Chem. 274: 9133-9136, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10092583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10092583</a>] [<a href="https://doi.org/10.1074/jbc.274.14.9133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10092583">Brodbeck et al. (1999)</a> showed that PKB-gamma had low basal activity following transfection into human embryonic kidney cells, but its activity was stimulated 67-fold by pervanadate, an insulin (INS; <a href="/entry/176730">176730</a>) mimetic. Mutation of thr305 to ala in the activation loop of PKB-gamma completely ablated its activation, whereas mutation of the C-terminal regulatory site, ser472, reduced but did not abolish activation by pervanadate. Activation of PKB-gamma by insulin required PI3K (see PIK3CG; <a href="/entry/601232">601232</a>) and was entirely due to phosphorylation at thr305. Removal of the PH domain of PKB-gamma made phosphorylation of thr305 independent of PI3K activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10092583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Chinese hamster ovary cells expressing human insulin receptor (INSR; <a href="/entry/147670">147670</a>) and AKT3, <a href="#10" class="mim-tip-reference" title="Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A. <strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong> Biochem. Biophys. Res. Commun. 257: 906-910, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208883</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208883">Nakatani et al. (1999)</a> showed that insulin stimulated AKT3 activity and phosphorylation of AKT3 on thr305 and ser472. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A. <strong>Somatic activation of AKT3 causes hemispheric developmental brain malformations.</strong> Neuron 74: 41-48, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22500628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22500628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22500628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.03.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22500628">Poduri et al. (2012)</a> compared the expression levels of the AKT1, AKT2, and AKT3 genes by RNA-seq analysis of the perisylvian cortex of the human brain at 9 weeks' gestation, during active neurogenesis, and found that the AKT3 gene is expressed at higher levels than the AKT1 and AKT2 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22500628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 assess the impact of AKT3, PIK3R2 (<a href="/entry/603157">603157</a>), and PIK3CA (<a href="/entry/171834">171834</a>) mutations in individuals with megalencephaly on PI3K activity, <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> used immunostaining to compare PIP3 amounts in lymphoblastoid cell lines derived from 4 mutation carriers with megalencephaly to those in control and PTEN-mutant cells. Consistent with elevated PI3K activity, and similar to what is seen with PTEN (<a href="/entry/601728">601728</a>) loss, all 3 lines with PIK3R2 or PIK3CA mutations showed significantly more PIP3 staining than control cells, as well as greater localization of active phosphoinositide-dependent kinase-1 (PDPK1; <a href="/entry/605213">605213</a>) to the cell membrane. Treatment with the PI3K inhibitor PI-103 resulted in less PIP3 in the PIK3R2 G373R (<a href="/entry/603157#0001">603157.0001</a>) and PIK3CA glu453del (<a href="/entry/171834#0014">171834.0014</a>) mutant lines, confirming that these results are PI3K-dependent. <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> found no evidence for increased PI3K activity in the AKT3-mutant line, consistent with a mutation affecting a downstream effector of PI3K. Protein blot analysis showed higher amounts of phosphorylated S6 protein and 4E-BP1 in all mutant cell lines compared to controls. Although PI-103 treatment reduced S6 phosphorylation in control and mutant lines, the latter showed relative resistance to PI3K inhibition, consistent with elevated signaling through the pathway. <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> concluded that the megalencephaly-associated mutations result in higher PI3K activity and PI3K-mTOR signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 determine whether individuals with hemimegalencephaly and a mutation in PIK3CA (E545K; <a href="/entry/171834#0003">171834.0003</a>), AKT3 (E17K; <a href="#0003">611223.0003</a>), or MTOR (C1483Y) have aberrant mTOR (<a href="/entry/601231">601231</a>) signaling, <a href="#6" class="mim-tip-reference" title="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> immunostained brain sections of such cases with an antibody specific to the phosphorylated epitope of the S6 protein in a standard assay for the activation of mTOR signaling. Cells with the morphology of cytomegalic neurons were strongly labeled for phosphorylated S6 in the 3-prime-diaminobenzidine (DAB) staining of HME brains. In addition, <a href="#6" class="mim-tip-reference" title="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> coimmunostained for the neuronal marker MAP2, comparing samples with age-matched, similarly processed non-HME cortical hemisphere, and found a marked increase in the number of cells that were positive for phosphorylated S6 and greater intensity of staining for phosphorylated S6 in cytomegalic neurons of HME cases. <a href="#6" class="mim-tip-reference" title="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> concluded that these mutations are associated with increased mTOR signaling in affected brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 pull-down assay, <a href="#5" class="mim-tip-reference" title="Ko, H. R., Jin, E.-J., Lee, S. B., Kim, C. K., Yun, T., Cho, S.-W., Park, K. W., Ahn, J.-Y. <strong>SIAH1 ubiquitin ligase mediates ubiquitination and degradation of Akt3 in neural development.</strong> J. Biol. Chem. 294: 15435-15445, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471318</a>] [<a href="https://doi.org/10.1074/jbc.RA119.009618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31471318">Ko et al. (2019)</a> showed that rat Siah1 (<a href="/entry/602212">602212</a>) interacted directly with AKT proteins, particularly Akt3. Siah1 functioned as an E3 ligase for polyubiquitination and subsequent proteasomal degradation of Akt3. In developing rat hippocampal neurons, Akt3 was enriched in the axonal shaft and branches, but not growth cone tips, and contributed to proper axon growth and branches. Siah1 regulated the distribution and function of Akt3 in growing neurites through ubiquitin-proteasome system (UPS)-mediated degradation in axon development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Fusion Gene in Breast Cancer</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., Lawrence, M. S., Sivachenko, A. Y., Sougnez, C., Zou, L., Cortes, M. L., Fernandez-Lopez, J. C., and 35 others. <strong>Sequence analysis of mutations and translocations across breast cancer subtypes.</strong> Nature 486: 405-409, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722202[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/nature11154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722202">Banerji et al. (2012)</a> reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. They identified a recurrent MAGI3/AKT3 fusion enriched in triple-negative breast cancers (TNBCs), which lack estrogen receptors (<a href="/entry/133430">133430</a>), progesterone receptors (<a href="/entry/607311">607311</a>), and ERBB2 (<a href="/entry/611223">611223</a>) expression. The MAGI3/AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22722202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 2</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> performed exome sequencing in an individual with clinical features overlapping both megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2; <a href="/entry/615937">615937</a>) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; <a href="/entry/602501">602501</a>) and his parents and identified a de novo mutation in the AKT3 gene (R465W; <a href="#0001">611223.0001</a>). Sanger sequencing of the AKT3 gene in another 40 individuals with megalencephaly (many subjects in this series had asymmetric brain enlargement, and several were diagnosed with hemimegalencephaly) identified a different de novo mutation in this gene in another individual with MPPH (N229S; <a href="#0002">611223.0002</a>). <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> suggested that the AKT3 gene is a rare cause of megalencephaly (p = 0.002, calculated as the likelihood of observing a second de novo mutation in the AKT3 gene). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 8 samples of brain tissue from individuals with hemimegalencephaly (HME), <a href="#11" class="mim-tip-reference" title="Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A. <strong>Somatic activation of AKT3 causes hemispheric developmental brain malformations.</strong> Neuron 74: 41-48, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22500628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22500628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22500628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.03.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22500628">Poduri et al. (2012)</a> identified somatic duplications of chromosome 1q encompassing the AKT3 gene in 2. Sequencing of the AKT3 gene in the other 6 samples identified 1 with a known activating mutation (E17K; <a href="#0003">611223.0003</a>); the mutation was not detectable in blood from this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22500628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> performed whole-exome sequencing on brain and peripheral blood DNA from 5 HME cases and identified 3 missense mutations: one in the PIK3CA gene (E545K; <a href="/entry/171834#0003">171834.0003</a>), one in the AKT3 gene (E17K; <a href="#0003">611223.0003</a>), and one in the MTOR gene (C1483Y). The individual with the MTOR gene mutation also carried a diagnosis of hypomelanosis of Ito (<a href="/entry/300337">300337</a>). <a href="#6" class="mim-tip-reference" title="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> then used a modified single base-extension protocol followed by mass spectrometry analysis to detect somatic mutations at a frequency as low as 3% in genetically heterogeneous samples. Reanalysis of the same DNA samples used for whole-exome sequencing again showed the absence of the mutant allele in blood but its presence in the brain, with similar mutation burden as that detected with Illumina sequencing. These somatic mutations were detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample. Using the same technology, <a href="#6" class="mim-tip-reference" title="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> screened for these mutations in 15 other HME cases and identified 3 additional cases carrying the PIK3CA E545K variant, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Easton, R. M., Cho, H., Roovers, K., Shineman, D. W., Mizrahi, M., Forman, M. S., Lee, V. M.-Y., Szabolcs, M., de Jong, R., Oltersdorf, T., Ludwig, T., Efstratiadis, A., Birnbaum, M. J. <strong>Role for Akt3/protein kinase B-gamma in attainment of normal brain size.</strong> Molec. Cell Biol. 25: 1869-1878, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15713641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15713641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15713641[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.25.5.1869-1878.2005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15713641">Easton et al. (2005)</a> found that Akt3-null mice had a selective 20% decrease in brain size due to smaller and fewer cells. This was in contrast to Akt1 (<a href="/entry/164730">164730</a>)-null mice, who showed a proportional decrease in the size of all organs in addition to the brain. Mammalian target of rapamycin (MTOR; <a href="/entry/601231">601231</a>) signaling was attenuated in the brains of Akt3-null mice, but not Akt1-null mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth. The findings showed the importance of insulin signaling through PI3K and the Akt genes for the regulation of cell and organ growth in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15713641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Nmf350 mouse mutation, which was obtained in an N-ethyl-N-nitrosourea mutagenesis screen, causes low seizure threshold, sporadic tonic-clonic seizures, brain enlargement, and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. <a href="#13" class="mim-tip-reference" title="Tokuda, S., Mahaffey, C. L., Monks, B., Faulkner, C. R., Birnbaum, M. J., Danzer, S. C., Frankel, W. N. <strong>A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice.</strong> Hum. Molec. Genet. 20: 988-999, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21159799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21159799</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21159799[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21159799">Tokuda et al. (2011)</a> identified Nmf350 as an asp219-to-val (D219V) mutation within the kinase domain of Akt3. In vitro kinase assays revealed that Akt3(Nmf350) had higher enzymatic activity than wildtype Akt3 in transfected HEK cells. Dentate gyrus of Nmf350 mice showed elevated content of phosphorylated ribosomal protein S6 (RPS6; <a href="/entry/180460">180460</a>), suggesting enhanced Akt signaling in hippocampus. In contrast with Nmf350 mice, Akt3 -/- mice exhibited elevated seizure threshold. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21159799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> performed exome sequencing in an individual with clinical features overlapping megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2; <a href="/entry/615937">615937</a>) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; <a href="/entry/602501">602501</a>) and identified a de novo 1393C-T transition in the AKT3 gene, resulting in an arg465-to-trp (R465W) substitution. The mutation was not found in his parents. This patient (LR08-018) had previously been reported by <a href="#7" class="mim-tip-reference" title="Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., Lev, D., Kramer, N., Hopkins, E., Graham, J. M., Jr., Dobyns, W. B. <strong>Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.</strong> Am. J. Med. Genet. 158A: 269-291, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228622</a>] [<a href="https://doi.org/10.1002/ajmg.a.34402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228622">Mirzaa et al. (2012)</a>. Also see <a href="#0002">611223.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22228622+22729224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 40 individuals with megalencephaly (many with asymmetric brain enlargement, and several diagnosed with hemimegalencephaly), <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> performed Sanger sequencing of the AKT3 gene and identified a de novo 686A-G transition, resulting in an asn229-to-ser (N229S) substitution, in 1 individual with MPPH2 (<a href="/entry/615937">615937</a>). <a href="#12" class="mim-tip-reference" title="Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. <strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong> Nature Genet. 44: 934-940, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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/ng.2331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729224">Riviere et al. (2012)</a> suggested that the AKT3 gene is a rare cause of megalencephaly (p = 0.002, calculated as the likelihood of observing a second de novo mutation in the AKT3 gene). See <a href="#0001">611223.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H. <strong>AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter)</strong> Clin. Genet. 85: 396-398, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23745724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23745724</a>] [<a href="https://doi.org/10.1111/cge.12188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23745724">Nakamura et al. (2014)</a> identified a de novo heterozygous N229S mutation in a 2-month-old boy with macrocephaly, cutis marmorata of the distal extremities, and hyperextensibility of the skin. Brain MRI at age 7 days showed right-dominant polymicrogyria, and at 2 months showed a thin corpus callosum and progressive hydrocephalus. <a href="#9" class="mim-tip-reference" title="Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H. <strong>AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter)</strong> Clin. Genet. 85: 396-398, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23745724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23745724</a>] [<a href="https://doi.org/10.1111/cge.12188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23745724">Nakamura et al. (2014)</a> stated that the phenotype was compatible with MCAP; however, the patient had only a skin capillary malformation. <a href="#9" class="mim-tip-reference" title="Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H. <strong>AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter)</strong> Clin. Genet. 85: 396-398, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23745724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23745724</a>] [<a href="https://doi.org/10.1111/cge.12188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23745724">Nakamura et al. (2014)</a> concluded that MPPH and MCAP show significant phenotypic overlap and have a common genetic basis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23745724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2, 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">rs397514606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514606;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=rs397514606" 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=rs397514606" 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=RCV000033037 OR RCV001836719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033037, RCV001836719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033037...</a>
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<p><a href="#11" class="mim-tip-reference" title="Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A. <strong>Somatic activation of AKT3 causes hemispheric developmental brain malformations.</strong> Neuron 74: 41-48, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22500628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22500628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22500628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.03.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22500628">Poduri et al. (2012)</a> sequenced the AKT3 gene as a candidate gene in 8 samples of brain tissue from patients with hemimegalencephaly (HME) (see MPPH2, <a href="/entry/615937">615937</a>) and identified 1 with a 49G-A transition resulting in a glu17-to-lys mutation (E17K) substitution. This mutation was not detectable in DNA derived from the patient's leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22500628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. <strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong> Nature Genet. 44: 941-945, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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/ng.2329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22729223">Lee et al. (2012)</a> performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with HME and identified the E17K mutation in the AKT3 gene in 1. The mutant allele was absent in blood but present in the brain, with a mutation burden of 40.4%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22729223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Ko, H. R., Jin, E.-J., Lee, S. B., Kim, C. K., Yun, T., Cho, S.-W., Park, K. W., Ahn, J.-Y. <strong>SIAH1 ubiquitin ligase mediates ubiquitination and degradation of Akt3 in neural development.</strong> J. Biol. Chem. 294: 15435-15445, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471318</a>] [<a href="https://doi.org/10.1074/jbc.RA119.009618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31471318">Ko et al. (2019)</a> found that the E17K mutation in AKT3 resulted in decreased affinity for interaction with SIAH1 (<a href="/entry/602212">602212</a>). E17K-AKT3 escaped UPS-dependent degradation mediated by SIAH1, leading to improper neural development with dysmorphic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Banerji2012" class="mim-anchor"></a>
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Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., Lawrence, M. S., Sivachenko, A. Y., Sougnez, C., Zou, L., Cortes, M. L., Fernandez-Lopez, J. C., and 35 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722202[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=22722202" 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/nature11154" target="_blank">Full Text</a>]
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Boland, E., Clayton-Smith, J., Woo, V. G., McKee, S., Manson, F. D. C., Medne, L., Zackai, E., Swanson, E. A., Fitzpatrick, D., Millen, K. J., Sherr, E. H., Dobyns, W. B., Black, G. C. M.
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<strong>Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.</strong>
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Am. J. Hum. Genet. 81: 292-303, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668379[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=17668379" 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/10.1086/519999" target="_blank">Full Text</a>]
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Brodbeck, D., Cron, P., Hemmings, B. A.
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<strong>A human protein kinase B-gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain.</strong>
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J. Biol. Chem. 274: 9133-9136, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10092583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10092583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10092583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.274.14.9133" target="_blank">Full Text</a>]
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Easton, R. M., Cho, H., Roovers, K., Shineman, D. W., Mizrahi, M., Forman, M. S., Lee, V. M.-Y., Szabolcs, M., de Jong, R., Oltersdorf, T., Ludwig, T., Efstratiadis, A., Birnbaum, M. J.
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<strong>Role for Akt3/protein kinase B-gamma in attainment of normal brain size.</strong>
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Molec. Cell Biol. 25: 1869-1878, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15713641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15713641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15713641[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=15713641" 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.25.5.1869-1878.2005" target="_blank">Full Text</a>]
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Ko, H. R., Jin, E.-J., Lee, S. B., Kim, C. K., Yun, T., Cho, S.-W., Park, K. W., Ahn, J.-Y.
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<strong>SIAH1 ubiquitin ligase mediates ubiquitination and degradation of Akt3 in neural development.</strong>
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J. Biol. Chem. 294: 15435-15445, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.RA119.009618" target="_blank">Full Text</a>]
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Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G.
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<strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong>
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Nature Genet. 44: 941-945, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729223[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=22729223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2329" target="_blank">Full Text</a>]
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Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., Lev, D., Kramer, N., Hopkins, E., Graham, J. M., Jr., Dobyns, W. B.
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<strong>Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.34402" target="_blank">Full Text</a>]
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Murthy, S. S., Tosolini, A., Taguchi, T., Testa, J. R.
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<strong>Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization.</strong>
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Cytogenet. Cell Genet. 88: 38-40, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10773662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10773662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10773662" 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/10.1159/000015481" target="_blank">Full Text</a>]
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Nakamura2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H.
|
|
<strong>AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter)</strong>
|
|
Clin. Genet. 85: 396-398, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23745724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23745724</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23745724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.12188" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Nakatani1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A.
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<strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong>
|
|
Biochem. Biophys. Res. Commun. 257: 906-910, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208883</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208883" 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/10.1006/bbrc.1999.0559" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Poduri2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A.
|
|
<strong>Somatic activation of AKT3 causes hemispheric developmental brain malformations.</strong>
|
|
Neuron 74: 41-48, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22500628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22500628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22500628[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=22500628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2012.03.010" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Riviere2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others.
|
|
<strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong>
|
|
Nature Genet. 44: 934-940, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22729224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22729224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22729224[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=22729224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2331" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Tokuda2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tokuda, S., Mahaffey, C. L., Monks, B., Faulkner, C. R., Birnbaum, M. J., Danzer, S. C., Frankel, W. N.
|
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<strong>A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice.</strong>
|
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Hum. Molec. Genet. 20: 988-999, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21159799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21159799</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21159799[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=21159799" 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/ddq544" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Bao Lige - updated : 06/10/2021
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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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Cassandra L. Kniffin - updated : 8/12/2014<br>Patricia A. Hartz - updated : 3/26/2014<br>Nara Sobreira - updated : 11/21/2012<br>Ada Hamosh - updated : 7/20/2012<br>Cassandra L. Kniffin - updated : 4/17/2012<br>Victor A. McKusick - updated : 8/16/2007<br>Victor A. McKusick - updated : 7/26/2007
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 7/18/2007
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/11/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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mgross : 06/10/2021<br>carol : 11/21/2019<br>carol : 04/13/2016<br>carol : 4/12/2016<br>alopez : 8/19/2014<br>alopez : 8/19/2014<br>ckniffin : 8/12/2014<br>mcolton : 6/16/2014<br>ckniffin : 6/12/2014<br>mgross : 3/26/2014<br>mcolton : 3/25/2014<br>carol : 6/4/2013<br>carol : 11/21/2012<br>carol : 11/21/2012<br>carol : 11/21/2012<br>carol : 11/21/2012<br>alopez : 7/20/2012<br>terry : 5/2/2012<br>carol : 4/17/2012<br>ckniffin : 4/17/2012<br>wwang : 6/29/2011<br>alopez : 8/20/2007<br>terry : 8/16/2007<br>alopez : 7/30/2007<br>terry : 7/26/2007<br>mgross : 7/18/2007
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 611223
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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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AKT SERINE/THREONINE KINASE 3; AKT3
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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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V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 3<br />
|
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PROTEIN KINASE B, GAMMA; PKBG<br />
|
|
PKB-GAMMA
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
|
|
MAGI3/AKT3 FUSION GENE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: AKT3</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: 1q43-q44
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:243,488,233-243,851,079 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
|
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<tbody>
|
|
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
1q43-q44
|
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</span>
|
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</td>
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|
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<td>
|
|
<span class="mim-font">
|
|
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
615937
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Members of the AKT protein family, such as AKT3, are implicated in numerous biologic processes, including adipocyte and muscle differentiation, glycogen synthesis, glucose uptake, apoptosis, and cellular proliferation (Nakatani et al., 1999). </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Using mouse Pkb-gamma to screen several human cDNA libraries, followed by 5-prime RACE of a human brain cDNA library, Brodbeck et al. (1999) cloned AKT3, which they called PKB-gamma. The deduced 479-amino acid protein contains a pleckstrin (173570) homology (PH) domain, an activation loop, and a C-terminal hydrophobic domain. PKB-gamma shares 83% and 78% amino acid identity with human PKB-alpha (AKT1; 164730) and PKB-beta (AKT2; 164731), respectively, and more than 99% identity with mouse Pkb-gamma. Northern blot analysis detected transcripts of 6.5 and 8.5 kb in all adult tissues examined, with highest expression in brain, lung, and kidney and lowest expression in heart and liver. Transcripts of the same size were detected in all fetal tissues examined except kidney, with highest expression in heart, brain, and liver. </p><p>Independently, Nakatani et al. (1999) cloned AKT3. Northern blot analysis detected highest expression of 5.3- and 7.7-kb transcripts in brain, heart, and placenta, with weaker expression in skeletal muscle, kidney, and pancreas. </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Nakatani et al. (1999) determined that the AKT3 gene contains 2 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Using FISH, Murthy et al. (2000) mapped the AKT3 gene to chromosome 1q44. They mapped the mouse Akt3 gene to chromosome 1H4-H6. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>Deletions of 1q42-q44 (612337) have been reported in a variety of developmental abnormalities of brain, including microcephaly and agenesis of the corpus callosum. Boland et al. (2007) described detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These defined a 3.5-Mb critical region that was hypothesized to contain 1 or more genes that lead to agenesis of the corpus callosum and microcephaly when present in only 1 functional copy. Mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal microcephaly and agenesis of the corpus callosum demonstrated a breakpoint in this region that was situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine ortholog Akt3 is required for developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with agenesis of the corpus callosum did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of AKT3 in the developing central nervous system during mouse embryogenesis. Boland et al. (2007) concluded that thus, AKT3 represents an excellent candidate for developmental human microcephaly and agenesis of the corpus callosum, and suggested that haploinsufficiency causes postnatal microcephaly and agenesis of the corpus callosum. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Brodbeck et al. (1999) showed that PKB-gamma had low basal activity following transfection into human embryonic kidney cells, but its activity was stimulated 67-fold by pervanadate, an insulin (INS; 176730) mimetic. Mutation of thr305 to ala in the activation loop of PKB-gamma completely ablated its activation, whereas mutation of the C-terminal regulatory site, ser472, reduced but did not abolish activation by pervanadate. Activation of PKB-gamma by insulin required PI3K (see PIK3CG; 601232) and was entirely due to phosphorylation at thr305. Removal of the PH domain of PKB-gamma made phosphorylation of thr305 independent of PI3K activity. </p><p>Using Chinese hamster ovary cells expressing human insulin receptor (INSR; 147670) and AKT3, Nakatani et al. (1999) showed that insulin stimulated AKT3 activity and phosphorylation of AKT3 on thr305 and ser472. </p><p>Poduri et al. (2012) compared the expression levels of the AKT1, AKT2, and AKT3 genes by RNA-seq analysis of the perisylvian cortex of the human brain at 9 weeks' gestation, during active neurogenesis, and found that the AKT3 gene is expressed at higher levels than the AKT1 and AKT2 genes. </p><p>To assess the impact of AKT3, PIK3R2 (603157), and PIK3CA (171834) mutations in individuals with megalencephaly on PI3K activity, Riviere et al. (2012) used immunostaining to compare PIP3 amounts in lymphoblastoid cell lines derived from 4 mutation carriers with megalencephaly to those in control and PTEN-mutant cells. Consistent with elevated PI3K activity, and similar to what is seen with PTEN (601728) loss, all 3 lines with PIK3R2 or PIK3CA mutations showed significantly more PIP3 staining than control cells, as well as greater localization of active phosphoinositide-dependent kinase-1 (PDPK1; 605213) to the cell membrane. Treatment with the PI3K inhibitor PI-103 resulted in less PIP3 in the PIK3R2 G373R (603157.0001) and PIK3CA glu453del (171834.0014) mutant lines, confirming that these results are PI3K-dependent. Riviere et al. (2012) found no evidence for increased PI3K activity in the AKT3-mutant line, consistent with a mutation affecting a downstream effector of PI3K. Protein blot analysis showed higher amounts of phosphorylated S6 protein and 4E-BP1 in all mutant cell lines compared to controls. Although PI-103 treatment reduced S6 phosphorylation in control and mutant lines, the latter showed relative resistance to PI3K inhibition, consistent with elevated signaling through the pathway. Riviere et al. (2012) concluded that the megalencephaly-associated mutations result in higher PI3K activity and PI3K-mTOR signaling. </p><p>To determine whether individuals with hemimegalencephaly and a mutation in PIK3CA (E545K; 171834.0003), AKT3 (E17K; 611223.0003), or MTOR (C1483Y) have aberrant mTOR (601231) signaling, Lee et al. (2012) immunostained brain sections of such cases with an antibody specific to the phosphorylated epitope of the S6 protein in a standard assay for the activation of mTOR signaling. Cells with the morphology of cytomegalic neurons were strongly labeled for phosphorylated S6 in the 3-prime-diaminobenzidine (DAB) staining of HME brains. In addition, Lee et al. (2012) coimmunostained for the neuronal marker MAP2, comparing samples with age-matched, similarly processed non-HME cortical hemisphere, and found a marked increase in the number of cells that were positive for phosphorylated S6 and greater intensity of staining for phosphorylated S6 in cytomegalic neurons of HME cases. Lee et al. (2012) concluded that these mutations are associated with increased mTOR signaling in affected brain regions. </p><p>Using a pull-down assay, Ko et al. (2019) showed that rat Siah1 (602212) interacted directly with AKT proteins, particularly Akt3. Siah1 functioned as an E3 ligase for polyubiquitination and subsequent proteasomal degradation of Akt3. In developing rat hippocampal neurons, Akt3 was enriched in the axonal shaft and branches, but not growth cone tips, and contributed to proper axon growth and branches. Siah1 regulated the distribution and function of Akt3 in growing neurites through ubiquitin-proteasome system (UPS)-mediated degradation in axon development. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Fusion Gene in Breast Cancer</em></strong></p><p>
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Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. They identified a recurrent MAGI3/AKT3 fusion enriched in triple-negative breast cancers (TNBCs), which lack estrogen receptors (133430), progesterone receptors (607311), and ERBB2 (611223) expression. The MAGI3/AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor. </p><p><strong><em>Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 2</em></strong></p><p>
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Riviere et al. (2012) performed exome sequencing in an individual with clinical features overlapping both megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2; 615937) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and his parents and identified a de novo mutation in the AKT3 gene (R465W; 611223.0001). Sanger sequencing of the AKT3 gene in another 40 individuals with megalencephaly (many subjects in this series had asymmetric brain enlargement, and several were diagnosed with hemimegalencephaly) identified a different de novo mutation in this gene in another individual with MPPH (N229S; 611223.0002). Riviere et al. (2012) suggested that the AKT3 gene is a rare cause of megalencephaly (p = 0.002, calculated as the likelihood of observing a second de novo mutation in the AKT3 gene). </p><p>In 8 samples of brain tissue from individuals with hemimegalencephaly (HME), Poduri et al. (2012) identified somatic duplications of chromosome 1q encompassing the AKT3 gene in 2. Sequencing of the AKT3 gene in the other 6 samples identified 1 with a known activating mutation (E17K; 611223.0003); the mutation was not detectable in blood from this patient. </p><p>Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 HME cases and identified 3 missense mutations: one in the PIK3CA gene (E545K; 171834.0003), one in the AKT3 gene (E17K; 611223.0003), and one in the MTOR gene (C1483Y). The individual with the MTOR gene mutation also carried a diagnosis of hypomelanosis of Ito (300337). Lee et al. (2012) then used a modified single base-extension protocol followed by mass spectrometry analysis to detect somatic mutations at a frequency as low as 3% in genetically heterogeneous samples. Reanalysis of the same DNA samples used for whole-exome sequencing again showed the absence of the mutant allele in blood but its presence in the brain, with similar mutation burden as that detected with Illumina sequencing. These somatic mutations were detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample. Using the same technology, Lee et al. (2012) screened for these mutations in 15 other HME cases and identified 3 additional cases carrying the PIK3CA E545K variant, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Easton et al. (2005) found that Akt3-null mice had a selective 20% decrease in brain size due to smaller and fewer cells. This was in contrast to Akt1 (164730)-null mice, who showed a proportional decrease in the size of all organs in addition to the brain. Mammalian target of rapamycin (MTOR; 601231) signaling was attenuated in the brains of Akt3-null mice, but not Akt1-null mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth. The findings showed the importance of insulin signaling through PI3K and the Akt genes for the regulation of cell and organ growth in mammals. </p><p>The Nmf350 mouse mutation, which was obtained in an N-ethyl-N-nitrosourea mutagenesis screen, causes low seizure threshold, sporadic tonic-clonic seizures, brain enlargement, and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. Tokuda et al. (2011) identified Nmf350 as an asp219-to-val (D219V) mutation within the kinase domain of Akt3. In vitro kinase assays revealed that Akt3(Nmf350) had higher enzymatic activity than wildtype Akt3 in transfected HEK cells. Dentate gyrus of Nmf350 mice showed elevated content of phosphorylated ribosomal protein S6 (RPS6; 180460), suggesting enhanced Akt signaling in hippocampus. In contrast with Nmf350 mice, Akt3 -/- mice exhibited elevated seizure threshold. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>3 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 MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AKT3, ARG465TRP
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<br />
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SNP: rs587776935,
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ClinVar: RCV000033035, RCV000415230, RCV000622431, RCV001532107, RCV002251942, RCV004532479, RCV004668745
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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>Riviere et al. (2012) performed exome sequencing in an individual with clinical features overlapping megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2; 615937) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and identified a de novo 1393C-T transition in the AKT3 gene, resulting in an arg465-to-trp (R465W) substitution. The mutation was not found in his parents. This patient (LR08-018) had previously been reported by Mirzaa et al. (2012). Also see 611223.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AKT3, ASN229SER
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<br />
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SNP: rs397514605,
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ClinVar: RCV000033036, RCV000416600
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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 40 individuals with megalencephaly (many with asymmetric brain enlargement, and several diagnosed with hemimegalencephaly), Riviere et al. (2012) performed Sanger sequencing of the AKT3 gene and identified a de novo 686A-G transition, resulting in an asn229-to-ser (N229S) substitution, in 1 individual with MPPH2 (615937). Riviere et al. (2012) suggested that the AKT3 gene is a rare cause of megalencephaly (p = 0.002, calculated as the likelihood of observing a second de novo mutation in the AKT3 gene). See 611223.0001. </p><p>Nakamura et al. (2014) identified a de novo heterozygous N229S mutation in a 2-month-old boy with macrocephaly, cutis marmorata of the distal extremities, and hyperextensibility of the skin. Brain MRI at age 7 days showed right-dominant polymicrogyria, and at 2 months showed a thin corpus callosum and progressive hydrocephalus. Nakamura et al. (2014) stated that the phenotype was compatible with MCAP; however, the patient had only a skin capillary malformation. Nakamura et al. (2014) concluded that MPPH and MCAP show significant phenotypic overlap and have a common genetic basis. </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 MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2, 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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AKT3, GLU17LYS
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<br />
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SNP: rs397514606,
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ClinVar: RCV000033037, RCV001836719
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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>Poduri et al. (2012) sequenced the AKT3 gene as a candidate gene in 8 samples of brain tissue from patients with hemimegalencephaly (HME) (see MPPH2, 615937) and identified 1 with a 49G-A transition resulting in a glu17-to-lys mutation (E17K) substitution. This mutation was not detectable in DNA derived from the patient's leukocytes. </p><p>Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with HME and identified the E17K mutation in the AKT3 gene in 1. The mutant allele was absent in blood but present in the brain, with a mutation burden of 40.4%. </p><p>Ko et al. (2019) found that the E17K mutation in AKT3 resulted in decreased affinity for interaction with SIAH1 (602212). E17K-AKT3 escaped UPS-dependent degradation mediated by SIAH1, leading to improper neural development with dysmorphic neurons. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., Lawrence, M. S., Sivachenko, A. Y., Sougnez, C., Zou, L., Cortes, M. L., Fernandez-Lopez, J. C., and 35 others.
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<strong>Sequence analysis of mutations and translocations across breast cancer subtypes.</strong>
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Nature 486: 405-409, 2012.
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[PubMed: 22722202]
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[Full Text: https://doi.org/10.1038/nature11154]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boland, E., Clayton-Smith, J., Woo, V. G., McKee, S., Manson, F. D. C., Medne, L., Zackai, E., Swanson, E. A., Fitzpatrick, D., Millen, K. J., Sherr, E. H., Dobyns, W. B., Black, G. C. M.
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<strong>Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.</strong>
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Am. J. Hum. Genet. 81: 292-303, 2007.
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[PubMed: 17668379]
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[Full Text: https://doi.org/10.1086/519999]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Brodbeck, D., Cron, P., Hemmings, B. A.
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<strong>A human protein kinase B-gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain.</strong>
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J. Biol. Chem. 274: 9133-9136, 1999.
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[PubMed: 10092583]
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[Full Text: https://doi.org/10.1074/jbc.274.14.9133]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Easton, R. M., Cho, H., Roovers, K., Shineman, D. W., Mizrahi, M., Forman, M. S., Lee, V. M.-Y., Szabolcs, M., de Jong, R., Oltersdorf, T., Ludwig, T., Efstratiadis, A., Birnbaum, M. J.
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<strong>Role for Akt3/protein kinase B-gamma in attainment of normal brain size.</strong>
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Molec. Cell Biol. 25: 1869-1878, 2005.
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[PubMed: 15713641]
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[Full Text: https://doi.org/10.1128/MCB.25.5.1869-1878.2005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ko, H. R., Jin, E.-J., Lee, S. B., Kim, C. K., Yun, T., Cho, S.-W., Park, K. W., Ahn, J.-Y.
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<strong>SIAH1 ubiquitin ligase mediates ubiquitination and degradation of Akt3 in neural development.</strong>
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J. Biol. Chem. 294: 15435-15445, 2019.
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[PubMed: 31471318]
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[Full Text: https://doi.org/10.1074/jbc.RA119.009618]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G.
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<strong>De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.</strong>
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Nature Genet. 44: 941-945, 2012.
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[PubMed: 22729223]
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[Full Text: https://doi.org/10.1038/ng.2329]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., Lev, D., Kramer, N., Hopkins, E., Graham, J. M., Jr., Dobyns, W. B.
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<strong>Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.</strong>
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Am. J. Med. Genet. 158A: 269-291, 2012.
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[PubMed: 22228622]
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[Full Text: https://doi.org/10.1002/ajmg.a.34402]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Murthy, S. S., Tosolini, A., Taguchi, T., Testa, J. R.
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<strong>Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization.</strong>
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Cytogenet. Cell Genet. 88: 38-40, 2000.
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[PubMed: 10773662]
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[Full Text: https://doi.org/10.1159/000015481]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H.
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<strong>AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter)</strong>
|
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Clin. Genet. 85: 396-398, 2014.
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[PubMed: 23745724]
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[Full Text: https://doi.org/10.1111/cge.12188]
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Nakatani, K., Sakaue, H., Thompson, D. A., Weigel, R. J., Roth, R. A.
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<strong>Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site.</strong>
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Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A.
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<strong>Somatic activation of AKT3 causes hemispheric developmental brain malformations.</strong>
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Neuron 74: 41-48, 2012.
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[PubMed: 22500628]
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[Full Text: https://doi.org/10.1016/j.neuron.2012.03.010]
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Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others.
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<strong>De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.</strong>
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Nature Genet. 44: 934-940, 2012.
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[Full Text: https://doi.org/10.1038/ng.2331]
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Tokuda, S., Mahaffey, C. L., Monks, B., Faulkner, C. R., Birnbaum, M. J., Danzer, S. C., Frankel, W. N.
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<strong>A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice.</strong>
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Hum. Molec. Genet. 20: 988-999, 2011.
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[PubMed: 21159799]
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[Full Text: https://doi.org/10.1093/hmg/ddq544]
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