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Entry
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- *600286 - PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA
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- OMIM
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<p>
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<span class="h4">*600286</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#mapping">Mapping</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="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600286">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000241973;t=ENST00000255882" 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=5297" 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=600286" 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 class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000241973;t=ENST00000255882" 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_001362862,NM_001362863,NM_058004,XM_005261635,XM_011530226,XM_011530228,XM_047441408,XM_047441409,XM_047441410" 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_058004" 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=600286" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=08972&isoform_id=08972_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/PI4KA" 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/598193,2326227,32197216,32425423,189054544,193788242,194379522,332367963,348041302,530420153,768025081,768025088,929654722,998455153,1384865919,1384865969,2217339821,2217339825,2217339828,2462585012,2462585014,2462585016,2462585018,2462585020,2462585022,2462585024" 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/P42356" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5297" 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=ENSG00000241973;t=ENST00000255882" 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=PI4KA" 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=PI4KA" 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+5297" 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/PI4KA" 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:5297" 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/5297" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr22&hgg_gene=ENST00000255882.11&hgg_start=20707691&hgg_end=20858811&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600286[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 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=600286[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://gnomad.broadinstitute.org/gene/ENSG00000241973" 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=PI4KA" 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=PI4KA" 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=PI4KA" 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=PI4KA&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/PA162399305" 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:8983" 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/FBgn0267350.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:2448506" 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/PI4KA#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:2448506" 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/5297/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=5297" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00013557;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-080220-34" 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:5297" 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=PI4KA&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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600286
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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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PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
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PHOSPHATIDYLINOSITOL 4-KINASE, CATALYTIC, ALPHA; PIK4CA<br />
|
|
PI4K-ALPHA<br />
|
|
PHOSPHATIDYLINOSITOL 4-KINASE, TYPE III, ALPHA<br />
|
|
PI4KIII-ALPHA
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PI4KA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PI4KA</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/22/66?start=-3&limit=10&highlight=66">22q11.21</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:20707691-20858811&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">22:20,707,691-20,858,811</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<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>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619708,616531,619621" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/66?start=-3&limit=10&highlight=66">
|
|
22q11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastrointestinal defects and immunodeficiency syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619708"> 619708 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
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|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616531"> 616531 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spastic paraplegia 84, autosomal recessive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619621"> 619621 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
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</tbody>
|
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</table>
|
|
</div>
|
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</div>
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<p>The PI4Ka gene encodes phosphatidylinositol (PI) 4-kinase, which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Several forms of mammalian PI 4-kinases have been purified, characterized, and classified into types II and III. The type II enzymes have an apparent molecular mass of approximately 55 kD, are highly stimulated by detergent, and are inhibited by adenosine. The type III enzymes have an apparent molecular mass of greater than 200 kD, are less stimulated by detergent, and are not inhibited by adenosine (summary by <a href="#5" class="mim-tip-reference" title="Nakagawa, T., Goto, K., Kondo, H. <strong>Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 271: 12088-12094, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662589</a>] [<a href="https://doi.org/10.1074/jbc.271.20.12088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662589">Nakagawa et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8662589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR and by screening human placenta and fetal brain cDNA libraries, <a href="#9" class="mim-tip-reference" title="Wong, K., Cantley, L. C. <strong>Cloning and characterization of a human phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 269: 28878-28884, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7961848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7961848</a>]" pmid="7961848">Wong and Cantley (1994)</a> cloned cDNAs encoding a PI 4-kinase, which they named PI4K-alpha. The predicted 854-amino acid protein has a calculated molecular mass of 97 kD. It contains an ankyrin repeat, a lipid kinase unique domain, a pleckstrin-homology domain, and a lipid kinase catalytic domain. PI4K-alpha has high amino acid sequence similarity to the yeast PI 4-kinases STT4 and PIK1; it has less amino acid sequence similarity to the catalytic domains of mammalian and yeast PI 3-kinases (e.g., <a href="/entry/171834">171834</a>) and to the yeast TOR family of proteins. The enzymatic properties of PI4K-alpha were characteristic of type II PI 4-kinases. By Northern blot analysis, 7.5- and 3.5-kb PI4K-alpha transcripts were detected in all human tissues examined, with the highest levels in placenta and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7961848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Nakagawa, T., Goto, K., Kondo, H. <strong>Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 271: 12088-12094, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662589</a>] [<a href="https://doi.org/10.1074/jbc.271.20.12088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662589">Nakagawa et al. (1996)</a> cloned a PI 4-kinase cDNA from a rat brain cDNA library. The C-terminal amino acid sequence of the predicted 2,041-amino acid rat PI 4-kinase is 98% similar to the amino acid sequence of PI4K-alpha, the human PI 4-kinase cDNA described by <a href="#9" class="mim-tip-reference" title="Wong, K., Cantley, L. C. <strong>Cloning and characterization of a human phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 269: 28878-28884, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7961848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7961848</a>]" pmid="7961848">Wong and Cantley (1994)</a>. Northern blot analysis of adult rat tissues detected a 7.8-kb transcript in all tissues examined, except liver. Based on their similar amino acid sequences and mRNA expression patterns, <a href="#5" class="mim-tip-reference" title="Nakagawa, T., Goto, K., Kondo, H. <strong>Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 271: 12088-12094, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662589</a>] [<a href="https://doi.org/10.1074/jbc.271.20.12088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662589">Nakagawa et al. (1996)</a> suggested that PI4K-alpha and the rat PI 4-kinase represent alternatively spliced forms of the same molecule. The N-terminal region of the rat PI 4-kinase, which is absent in PI4K-alpha, contains 2 proline-rich regions and an SH3 domain. Western blot analysis of lysates from transfected mammalian cells indicated that the rat PI 4-kinase has a molecular mass of approximately 230 kD. <a href="#5" class="mim-tip-reference" title="Nakagawa, T., Goto, K., Kondo, H. <strong>Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.</strong> J. Biol. Chem. 271: 12088-12094, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662589</a>] [<a href="https://doi.org/10.1074/jbc.271.20.12088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662589">Nakagawa et al. (1996)</a> found that the rat PI 4-kinase has the enzymatic properties of type III PI 4-kinases. By in situ hybridization, they detected rat PI 4-kinase mRNA in the gray matter of the brain, with expression higher in fetal brain than in adult brain. Immunohistochemistry demonstrated that the protein is associated with the membranes of Golgi vesicles and vacuoles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7961848+8662589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 1/29/2016."None>Gross (2016)</a> mapped the PI4KA gene to chromosome 22q11.21 based on an alignment of the PI4KA sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF012872" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF012872</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#4" class="mim-tip-reference" title="Hammond, G. R. V., Fischer, M. J., Anderson, K. E., Holdich, J., Koteci, A., Balla, T., Irvine, R. F. <strong>PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity.</strong> Science 337: 727-730, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722250</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722250[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/10.1126/science.1222483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722250">Hammond et al. (2012)</a> used a combination of pharmacologic and chemical genetic approaches to probe the function of plasma membrane phosphatidylinositol 4-phosphate (PI4P), most of which was not required for the synthesis or functions of PI(4,5)P2. However, depletion of both lipids was required to prevent plasma membrane targeting of proteins that interact with acidic lipids or activation of the transient receptor potential vanilloid-1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P2, which may be fulfilled by a more general polyanionic lipid requirement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22722250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Chung, J., Nakatsu, F., Baskin, J. M., De Camilli, P. <strong>Plasticity of PI4KIII-alpha interactions at the plasma membrane.</strong> EMBO Rep. 16: 312-320, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25608530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25608530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25608530[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/10.15252/embr.201439151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25608530">Chung et al. (2015)</a> had previously found that EFR3B (<a href="/entry/616797">616797</a>) and TTC7B (<a href="/entry/620060">620060</a>) were required for targeting of PI4K3A to the plasma membrane. Using cotransfection and immunoprecipitation experiments with HeLa cells, they found that TMEM150A (<a href="/entry/616757">616757</a>) also interacted with PI4K3A and EFR3B, but not with TTC7B. Overexpression of TMEM150A in HeLa cells accelerated PI4K3A-dependent recovery of PI(4,5)P2 following its agonist-dependent depletion. <a href="#2" class="mim-tip-reference" title="Chung, J., Nakatsu, F., Baskin, J. M., De Camilli, P. <strong>Plasticity of PI4KIII-alpha interactions at the plasma membrane.</strong> EMBO Rep. 16: 312-320, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25608530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25608530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25608530[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/10.15252/embr.201439151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25608530">Chung et al. (2015)</a> concluded that TMEM150A displaces TTC7B from the PI4K3A-EFR3B complex, following initial targeting of PI4K3A to the plasma membrane, and stabilizes PI4K3A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25608530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By proteomic analysis in HeLa cells, <a href="#1" class="mim-tip-reference" title="Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., Messa, M., Baldassari, S., Assereto, S., Biancheri, R., Zara, F., Minetti, C., Raimondi, A., Simons, M., Walther, T. C., Reinisch, K. M., De Camilli, P. <strong>The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane.</strong> Nat. Cell Biol. 18: 132-138, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26571211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26571211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26571211[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/ncb3271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26571211">Baskin et al. (2016)</a> confirmed that TTC7B, ERF3A (<a href="/entry/611798">611798</a>), and EFR3B were components of the PI4KIII-alpha complex. They identified FAM126A (<a href="/entry/610531">610531</a>) or FAM126B (HYCC2) as additional components of the PI4KIII-alpha complex. TTC7B played a central role in bridging PI4KIII-alpha to EFR3B. Moreover, FAM126A bound directly to TTC7B through its N-terminal portion to form a heterodimer, and FAM126A-TTC7B bound to PI4KIII-alpha simultaneously to form a ternary complex. Interaction of PI4KIII-alpha with TTC7B and FAM126A appeared to stabilize the PI4KIII-alpha fold and stimulate catalytic activity. Moreover, FAM126A loss or reduction in mouse or human destabilized and degraded PI4KIII-alpha complex components and affected PI4KIII-alpha complex assembly and PI4KIII-alpha-mediated PtdIns4P synthesis at the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26571211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neurodevelopmental Disorder With Spasticity, Hypomyelinating Leukodystrophy, And Brain Abnormalities</em></strong></p><p>
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In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see <a href="/entry/616531">616531</a>), <a href="#6" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. <strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong> Hum. Molec. Genet. 24: 3732-3741, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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/ddv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25855803">Pagnamenta et al. (2015)</a> identified compound heterozygous mutations in the PI4KA gene (R796X, <a href="#0001">600286.0001</a> and D1854N, <a href="#0002">600286.0002</a>). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development. All 3 fetuses were diagnosed in utero with multiple congenital anomalies, and the pregnancies terminated between 16 and 34 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25855803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 unrelated patients (patients 1-8) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., <a href="#0002">600286.0002</a>-<a href="#0006">600286.0006</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro studies of cells derived from some of the patients indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. None of the patients had 2 complete loss-of-function mutations, suggesting that complete loss of PI4KA would be incompatible with life. The authors concluded that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> noted that the fetuses reported by <a href="#6" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. <strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong> Hum. Molec. Genet. 24: 3732-3741, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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/ddv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25855803">Pagnamenta et al. (2015)</a> were compound heterozygous for 2 loss-of-function variants and may represent the most severe end of the phenotypic spectrum resulting from PI4KA mutations. <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> pointed out that among their patients, no abnormalities were detected during pregnancy. Although <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> stated that among their patients, they did not find a patient with 2 loss-of-function variants, 1 patient (patient 8) was homozygous for one of the variants (D1854N; <a href="#0002">600286.0002</a>) carried by the fetuses studied by <a href="#6" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. <strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong> Hum. Molec. Genet. 24: 3732-3741, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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/ddv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25855803">Pagnamenta et al. (2015)</a>, which <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> stated carried 2 loss-of-function variants. <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> suggested that the fact that the D1854N variant in homozygosity led to a milder phenotype than that of the fetuses strongly suggests that this missense variant would not cause a complete loss of function, and that a certain degree of residual PI4KA activity was retained in patient 8. Additionally, patient 8 had polymicrogyria, as did the fetuses, suggesting that the D1854N variant may be specifically associated with that developmental brain abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34415322+25855803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6 unrelated patients (families 3-8) with NEDSPLB, <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a> identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., <a href="#0002">600286.0002</a>; <a href="#0011">600286.0011</a>-<a href="#0014">600286.0014</a>). The mutations were found by exome sequencing and segregated with the disorder in the families; the patients were ascertained through the GeneMatcher Program. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. In addition to developmental delay, spasticity, and leukoencephalopathy, some patients had inflammatory bowel disease and/or immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Autosomal Recessive Spastic Paraplegia 84</em></strong></p><p>
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In 2 unrelated patients (patients 9 and 10) with autosomal recessive spastic paraplegia-84 (SPG84; <a href="/entry/619621">619621</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified compound heterozygous mutations in the PI4KA gene (<a href="#0006">600286.0006</a>-<a href="#0009">600286.0009</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed decreased PI4K protein levels compared to controls. Further studies showed that patients cells had decreased PI4KA activity compared to controls, consistent with the mutations being hypomorphic alleles. The authors postulated that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Gastrointestinal Defects And Immunodeficiency Syndrome 2</em></strong></p><p>
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In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; <a href="/entry/619708">619708</a>), <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a> identified a homozygous missense mutation in the PI4KA gene (Y1623D; <a href="#0010">600286.0010</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (<a href="/entry/609332">609332</a>), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; <a href="/entry/243150">243150</a>). All patients with GIDI2 died of intestinal atresia in the first weeks of life; 2 patients had evidence of an immunodeficiency with lymphopenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600286[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
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<p>In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with NEDSPLB (<a href="/entry/616531">616531</a>) manifest as perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA), <a href="#6" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. <strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong> Hum. Molec. Genet. 24: 3732-3741, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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/ddv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25855803">Pagnamenta et al. (2015)</a> identified compound heterozygous mutations in the PI4KA gene: a c.2386C-T transition (c.2386C-T, NM_058004.3) in exon 20, resulting in an arg796-to-ter (R796X) substitution, inherited from the unaffected father, and a c.5560G-A transition in exon 48, resulting in an asp1854-to-asn (D1854N; <a href="#0002">600286.0002</a>) substitution at a highly conserved residue in the kinase-binding domain, inherited from the unaffected mother. The mutations, which were found by a combination of exome sequencing and linkage analysis, were confirmed by Sanger sequencing. Neither mutation was found in 274 in-house genomes of mixed ancestry or in 500 Dutch genomes, but both were detected once in the ExAC database. Parental blood samples detected both mutations at the RNA level. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The fetuses were electively terminated between 16 and 34 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25855803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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"><span class="text-primary">●</span> rs747119727 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747119727;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs747119727?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs747119727" 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=rs747119727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.5560G-A transition (c.5560G-A, NM_058004.3) in the PI4KA gene, resulting in an asp1854-to-asn (D1854N) substitution, that was found in compound heterozygous state in tissue samples from 3 fetuses with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see <a href="/entry/616531">616531</a>) by <a href="#6" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. <strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong> Hum. Molec. Genet. 24: 3732-3741, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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/ddv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25855803">Pagnamenta et al. (2015)</a>, see <a href="#0001">600286.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25855803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 5-year-old boy (patient 8), born of consanguineous Turkish parents, with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified a homozygous D1854N substitution in the PI4KA gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed. The patient had spastic tetraparesis, severe developmental delay, and polymicrogyria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 13-year-old girl (P3), born of consanguineous Turkish parents, with NEDSPLB, <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a> identified a homozygous D1854N mutation in the PI4KA gene that segregated with the disorder in the family. Functional studies of the variant were not performed. The patient presented on the first day of life with refractory seizures and later showed severe global developmental delay, central hypotonia, peripheral spasticity, hypomyelinating leukodystrophy, immunodeficiency, and suspected inflammatory bowel disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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"><span class="text-primary">●</span> rs747391554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747391554;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs747391554?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs747391554" 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=rs747391554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4-year-old girl (patient 1) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified compound heterozygous mutations in the PI4KA gene: a 1-bp duplication (c.2624dupC) in exon 22, resulting in a frameshift and premature termination (Pro876SerfsTer36), and a c.3454G-A transition in exon 30, resulting in a glu1152-to-lys (E1152K; <a href="#0004">600286.0004</a>) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.2624dupC mutation was found once in the gnomAD v2.1.1 database (1 of 250,576 alleles). The E1154K mutation was found once in the gnomAD v2.1.1 database (1 of 251,262 alleles). In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1351749039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1351749039;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1351749039?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1351749039" 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=rs1351749039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.3454G-A transition in the PI4KA gene, resulting in a glu1152-to-lys (E1152K; <a href="#0004">600286.0004</a>) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>) by <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a>, see <a href="#0003">600286.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001785410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001785410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001785410</a>
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<p>In a 19-year-old woman (patient 4) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified compound heterozygous mutations in the PI4KA gene: a c.3592G-A transition in exon 31, resulting in an ala1198to-thr (A1198T) substitution at a conserved residue, and a 4-bp deletion in exon 53 (c.6156_6159delGACA; <a href="#0006">600286.0006</a>), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD v2.1.1 database. Western blot analysis of patient cells showed decreased protein levels compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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"><span class="text-primary">●</span> rs139598272 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs139598272;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs139598272?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs139598272" 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=rs139598272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>) by <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a>, see <a href="#0003">600286.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; <a href="/entry/619621">619621</a>), see <a href="#0007">600286.0007</a>.</p>
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<strong>.0007 SPASTIC PARAPLEGIA 84, AUTOSOMAL RECESSIVE</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">rs1925715512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1925715512;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=rs1925715512" 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=rs1925715512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 42-year-old man (patient 9) with autosomal recessive spastic paraplegia-84 (SPG84; <a href="/entry/619621">619621</a>), <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified compound heterozygous mutations in the PI4KA gene: a 3-bp deletion (c.5459_5461delAAG) in exon 47, resulting in an in-frame deletion of conserved residue (Glu1820del, E1820del), and a 4-bp deletion (c.6156_6159delGACA; <a href="#0006">600286.0006</a>), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The Glu1820del mutation was not present in gnomAD v2.1.1, but was found in 1 of 143,164 alleles in v3. The c.6156_6159delGACA was not present in the gnomAD database. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs144363917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144363917;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs144363917?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs144363917" 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=rs144363917" 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=RCV001785414 OR RCV003479351 OR RCV004591566" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001785414, RCV003479351, RCV004591566" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001785414...</a>
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<p>In an 18-year-old man of Hispanic descent (patient 10), with autosomal recessive spastic paraplegia-84 (SPG84; <a href="/entry/619621">619621</a>) <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a> identified compound heterozygous missense mutations in the PI4KA gene: a c.4666G-A transition in exon 39, resulting in a val1556-to-met (V1556M) substitution, and a c.5159C-T transition in exon 44, resulting in a thr1720-to-ile (T1720I; <a href="#0009">600286.0009</a>). Both mutations occurred at conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For discussion of the c.5159C-T transition in the PI4KA gene, resulting in a thr1720-to-ile (T1720I) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; <a href="/entry/619621">619621</a>) by <a href="#8" class="mim-tip-reference" title="Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. <strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong> Brain 144: 2659-2669, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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/brain/awab124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415322">Verdura et al. (2021)</a>, see <a href="#0008">600286.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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PI4KA, TYR1623ASP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs776650691;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs776650691</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs776650691 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs776650691;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs776650691?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs776650691" 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=rs776650691" 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=RCV001822068" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001822068" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001822068</a>
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<p>In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; <a href="/entry/619708">619708</a>), <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a> identified a homozygous c.4867T-G transversion (c.4867T-G, NM_058004.3) in the PI4KA gene, resulting in a tyr1623-to-asp (Y1623D) substitution at a conserved residue distal from the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the heterozygous state only in the gnomAD database (8.0 x 10(-6)). In vitro studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (<a href="/entry/609332">609332</a>), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; <a href="/entry/243150">243150</a>). All infants died in the first weeks of life; 2 patients had evidence of an immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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">rs2147171210 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147171210;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=rs2147171210" 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=rs2147171210" 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=RCV001822069" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001822069" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001822069</a>
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<p>In a 5-year-old girl (family 4) of Indian descent with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a> identified compound heterozygous mutations in the PI4KA gene: a c.5774G-A transition (c.5774G-A, NM_058004.3), resulting in a gly1925-to-glu (G1925E) substitution at a conserved residue in the catalytic domain, and a 1-bp deletion (c.6065delG; <a href="#0012">600286.0012</a>) in exon 52, predicted to result in a frameshift and premature termination (Arg2022GlnfsTer36). The mutations, which were found by trio-based whole-genome sequencing, segregated with the disorder in the family. Both were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. The patient had developmental delay, spasticity, leukoencephalopathy, colitis, and autoimmune enteropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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"><span class="text-primary">●</span> rs1419816068 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1419816068;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1419816068?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1419816068" 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=rs1419816068" 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=RCV001822070" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001822070" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001822070</a>
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<p>For discussion of the 1-bp deletion (c.6065delG, NM_058004.3) in exon 52 of the PI4KA gene, resulting in a frameshift and premature termination (Arg2022GlnfsTer36), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>) by <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a>, see <a href="#0011">600286.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0013 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
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PI4KA, LEU777PRO (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1490645147;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1490645147</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1490645147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1490645147;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1490645147?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1490645147" 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=rs1490645147" 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=RCV001822071" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001822071" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001822071</a>
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<p>In a 21-year-old German woman (family 7) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>), <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a>m identified compound heterozygous mutations in the PI4KA gene: a c.2330T-C transition (c.2330T-C, NM_058004.3), resulting in a leu777-to-pro (L777P) substitution, and a c.3571C-T transition in exon 31, resulting in a gln1191-to-ter (Q1191X; <a href="#0014">600286.0014</a>) substitution. L777P was found at a low frequency in the heterozygous state in the gnomAD database (4 x 10(-6)), whereas Q1191X was not found in gnomAD. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but molecular modeling predicted that they would interfere with PI4KA function. The patient had global developmental delay, seizures, spasticity, and leukoencephalopathy. She did not have gastrointestinal disease or immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0014 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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">rs2147287553 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147287553;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=rs2147287553" 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=rs2147287553" 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=RCV001822072" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001822072" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001822072</a>
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<p>For discussion of the c.3571C-T transition (c.3571C-T, NM_058004.3) in exon 31, resulting in a gln1191-to-ter (Q1191X) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; <a href="/entry/616531">616531</a>) by <a href="#7" class="mim-tip-reference" title="Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. <strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong> Brain 144: 3597-3610, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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/brain/awab313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34415310">Salter et al. (2021)</a>, see <a href="#0013">600286.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34415310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., Messa, M., Baldassari, S., Assereto, S., Biancheri, R., Zara, F., Minetti, C., Raimondi, A., Simons, M., Walther, T. C., Reinisch, K. M., De Camilli, P.
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[<a href="https://doi.org/10.1038/ncb3271" target="_blank">Full Text</a>]
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<a id="Chung2015" class="mim-anchor"></a>
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Chung, J., Nakatsu, F., Baskin, J. M., De Camilli, P.
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<strong>Plasticity of PI4KIII-alpha interactions at the plasma membrane.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25608530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25608530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25608530[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=25608530" 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/10.15252/embr.201439151" target="_blank">Full Text</a>]
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<a id="Gross2016" class="mim-anchor"></a>
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 1/29/2016.
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Hammond, G. R. V., Fischer, M. J., Anderson, K. E., Holdich, J., Koteci, A., Balla, T., Irvine, R. F.
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<strong>PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity.</strong>
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Science 337: 727-730, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722250</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722250[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=22722250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1222483" target="_blank">Full Text</a>]
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Nakagawa, T., Goto, K., Kondo, H.
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<strong>Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.</strong>
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J. Biol. Chem. 271: 12088-12094, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8662589" 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.271.20.12088" target="_blank">Full Text</a>]
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<a id="Pagnamenta2015" class="mim-anchor"></a>
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Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U.
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<strong>Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.</strong>
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Hum. Molec. Genet. 24: 3732-3741, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25855803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25855803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25855803[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=25855803" 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/ddv117" target="_blank">Full Text</a>]
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Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others.
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<strong>Biallelic PI4KA variants cause neurological, intestinal and immunological disease.</strong>
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Brain 144: 3597-3610, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415310[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=34415310" 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/brain/awab313" target="_blank">Full Text</a>]
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Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others.
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<strong>Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.</strong>
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Brain 144: 2659-2669, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34415322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34415322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34415322[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=34415322" 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/brain/awab124" target="_blank">Full Text</a>]
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Wong, K., Cantley, L. C.
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<strong>Cloning and characterization of a human phosphatidylinositol 4-kinase.</strong>
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J. Biol. Chem. 269: 28878-28884, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7961848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7961848</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7961848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bao Lige - updated : 08/07/2023
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Cassandra L. Kniffin - updated : 01/18/2022<br>Cassandra L. Kniffin - updated : 11/17/2021<br>Matthew B. Gross - updated : 1/29/2016<br>Patricia A. Hartz - updated : 1/14/2016<br>Cassandra L. Kniffin - updated : 8/24/2015<br>Ada Hamosh - updated : 8/29/2012<br>Patti M. Sherman - updated : 6/30/1998
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Victor A. McKusick : 1/6/1995
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mgross : 02/28/2023<br>mgross : 09/28/2022<br>alopez : 01/24/2022<br>ckniffin : 01/18/2022<br>alopez : 11/22/2021<br>ckniffin : 11/17/2021<br>carol : 02/08/2016<br>mgross : 1/29/2016<br>mgross : 1/14/2016<br>carol : 8/31/2015<br>mcolton : 8/25/2015<br>ckniffin : 8/24/2015<br>alopez : 9/4/2012<br>terry : 8/29/2012<br>alopez : 2/4/2009<br>carol : 3/18/2008<br>mgross : 12/8/2005<br>carol : 7/10/1998<br>psherman : 7/8/1998<br>carol : 6/30/1998<br>psherman : 6/30/1998<br>alopez : 9/26/1997<br>alopez : 9/8/1997<br>alopez : 9/5/1997<br>alopez : 6/5/1997<br>carol : 1/6/1995
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PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA
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PHOSPHATIDYLINOSITOL 4-KINASE, CATALYTIC, ALPHA; PIK4CA<br />
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PI4K-ALPHA<br />
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PHOSPHATIDYLINOSITOL 4-KINASE, TYPE III, ALPHA<br />
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PI4KIII-ALPHA
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<strong><em>HGNC Approved Gene Symbol: PI4KA</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: 22q11.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:20,707,691-20,858,811 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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22q11.21
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</span>
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</td>
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<td>
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<span class="mim-font">
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Gastrointestinal defects and immunodeficiency 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">
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619708
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
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</span>
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</td>
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<td>
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<span class="mim-font">
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616531
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Spastic paraplegia 84, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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619621
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The PI4Ka gene encodes phosphatidylinositol (PI) 4-kinase, which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Several forms of mammalian PI 4-kinases have been purified, characterized, and classified into types II and III. The type II enzymes have an apparent molecular mass of approximately 55 kD, are highly stimulated by detergent, and are inhibited by adenosine. The type III enzymes have an apparent molecular mass of greater than 200 kD, are less stimulated by detergent, and are not inhibited by adenosine (summary by Nakagawa et al., 1996). </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>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR and by screening human placenta and fetal brain cDNA libraries, Wong and Cantley (1994) cloned cDNAs encoding a PI 4-kinase, which they named PI4K-alpha. The predicted 854-amino acid protein has a calculated molecular mass of 97 kD. It contains an ankyrin repeat, a lipid kinase unique domain, a pleckstrin-homology domain, and a lipid kinase catalytic domain. PI4K-alpha has high amino acid sequence similarity to the yeast PI 4-kinases STT4 and PIK1; it has less amino acid sequence similarity to the catalytic domains of mammalian and yeast PI 3-kinases (e.g., 171834) and to the yeast TOR family of proteins. The enzymatic properties of PI4K-alpha were characteristic of type II PI 4-kinases. By Northern blot analysis, 7.5- and 3.5-kb PI4K-alpha transcripts were detected in all human tissues examined, with the highest levels in placenta and brain. </p><p>Nakagawa et al. (1996) cloned a PI 4-kinase cDNA from a rat brain cDNA library. The C-terminal amino acid sequence of the predicted 2,041-amino acid rat PI 4-kinase is 98% similar to the amino acid sequence of PI4K-alpha, the human PI 4-kinase cDNA described by Wong and Cantley (1994). Northern blot analysis of adult rat tissues detected a 7.8-kb transcript in all tissues examined, except liver. Based on their similar amino acid sequences and mRNA expression patterns, Nakagawa et al. (1996) suggested that PI4K-alpha and the rat PI 4-kinase represent alternatively spliced forms of the same molecule. The N-terminal region of the rat PI 4-kinase, which is absent in PI4K-alpha, contains 2 proline-rich regions and an SH3 domain. Western blot analysis of lysates from transfected mammalian cells indicated that the rat PI 4-kinase has a molecular mass of approximately 230 kD. Nakagawa et al. (1996) found that the rat PI 4-kinase has the enzymatic properties of type III PI 4-kinases. By in situ hybridization, they detected rat PI 4-kinase mRNA in the gray matter of the brain, with expression higher in fetal brain than in adult brain. Immunohistochemistry demonstrated that the protein is associated with the membranes of Golgi vesicles and vacuoles. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gross (2016) mapped the PI4KA gene to chromosome 22q11.21 based on an alignment of the PI4KA sequence (GenBank AF012872) with the genomic sequence (GRCh38).</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>Hammond et al. (2012) used a combination of pharmacologic and chemical genetic approaches to probe the function of plasma membrane phosphatidylinositol 4-phosphate (PI4P), most of which was not required for the synthesis or functions of PI(4,5)P2. However, depletion of both lipids was required to prevent plasma membrane targeting of proteins that interact with acidic lipids or activation of the transient receptor potential vanilloid-1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P2, which may be fulfilled by a more general polyanionic lipid requirement. </p><p>Chung et al. (2015) had previously found that EFR3B (616797) and TTC7B (620060) were required for targeting of PI4K3A to the plasma membrane. Using cotransfection and immunoprecipitation experiments with HeLa cells, they found that TMEM150A (616757) also interacted with PI4K3A and EFR3B, but not with TTC7B. Overexpression of TMEM150A in HeLa cells accelerated PI4K3A-dependent recovery of PI(4,5)P2 following its agonist-dependent depletion. Chung et al. (2015) concluded that TMEM150A displaces TTC7B from the PI4K3A-EFR3B complex, following initial targeting of PI4K3A to the plasma membrane, and stabilizes PI4K3A. </p><p>By proteomic analysis in HeLa cells, Baskin et al. (2016) confirmed that TTC7B, ERF3A (611798), and EFR3B were components of the PI4KIII-alpha complex. They identified FAM126A (610531) or FAM126B (HYCC2) as additional components of the PI4KIII-alpha complex. TTC7B played a central role in bridging PI4KIII-alpha to EFR3B. Moreover, FAM126A bound directly to TTC7B through its N-terminal portion to form a heterodimer, and FAM126A-TTC7B bound to PI4KIII-alpha simultaneously to form a ternary complex. Interaction of PI4KIII-alpha with TTC7B and FAM126A appeared to stabilize the PI4KIII-alpha fold and stimulate catalytic activity. Moreover, FAM126A loss or reduction in mouse or human destabilized and degraded PI4KIII-alpha complex components and affected PI4KIII-alpha complex assembly and PI4KIII-alpha-mediated PtdIns4P synthesis at the plasma membrane. </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>Neurodevelopmental Disorder With Spasticity, Hypomyelinating Leukodystrophy, And Brain Abnormalities</em></strong></p><p>
|
|
In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see 616531), Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene (R796X, 600286.0001 and D1854N, 600286.0002). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development. All 3 fetuses were diagnosed in utero with multiple congenital anomalies, and the pregnancies terminated between 16 and 34 weeks' gestation. </p><p>In 8 unrelated patients (patients 1-8) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002-600286.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro studies of cells derived from some of the patients indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. None of the patients had 2 complete loss-of-function mutations, suggesting that complete loss of PI4KA would be incompatible with life. The authors concluded that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development. </p><p>Verdura et al. (2021) noted that the fetuses reported by Pagnamenta et al. (2015) were compound heterozygous for 2 loss-of-function variants and may represent the most severe end of the phenotypic spectrum resulting from PI4KA mutations. Verdura et al. (2021) pointed out that among their patients, no abnormalities were detected during pregnancy. Although Verdura et al. (2021) stated that among their patients, they did not find a patient with 2 loss-of-function variants, 1 patient (patient 8) was homozygous for one of the variants (D1854N; 600286.0002) carried by the fetuses studied by Pagnamenta et al. (2015), which Verdura et al. (2021) stated carried 2 loss-of-function variants. Verdura et al. (2021) suggested that the fact that the D1854N variant in homozygosity led to a milder phenotype than that of the fetuses strongly suggests that this missense variant would not cause a complete loss of function, and that a certain degree of residual PI4KA activity was retained in patient 8. Additionally, patient 8 had polymicrogyria, as did the fetuses, suggesting that the D1854N variant may be specifically associated with that developmental brain abnormality. </p><p>In 6 unrelated patients (families 3-8) with NEDSPLB, Salter et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002; 600286.0011-600286.0014). The mutations were found by exome sequencing and segregated with the disorder in the families; the patients were ascertained through the GeneMatcher Program. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. In addition to developmental delay, spasticity, and leukoencephalopathy, some patients had inflammatory bowel disease and/or immunodeficiency. </p><p><strong><em>Autosomal Recessive Spastic Paraplegia 84</em></strong></p><p>
|
|
In 2 unrelated patients (patients 9 and 10) with autosomal recessive spastic paraplegia-84 (SPG84; 619621), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene (600286.0006-600286.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed decreased PI4K protein levels compared to controls. Further studies showed that patients cells had decreased PI4KA activity compared to controls, consistent with the mutations being hypomorphic alleles. The authors postulated that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development. </p><p><strong><em>Gastrointestinal Defects And Immunodeficiency Syndrome 2</em></strong></p><p>
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In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; 619708), Salter et al. (2021) identified a homozygous missense mutation in the PI4KA gene (Y1623D; 600286.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (609332), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; 243150). All patients with GIDI2 died of intestinal atresia in the first weeks of life; 2 patients had evidence of an immunodeficiency with lymphopenia. </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>14 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 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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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PI4KA, ARG796TER
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<br />
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SNP: rs777006911,
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gnomAD: rs777006911,
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ClinVar: RCV000190465
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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 tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with NEDSPLB (616531) manifest as perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA), Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene: a c.2386C-T transition (c.2386C-T, NM_058004.3) in exon 20, resulting in an arg796-to-ter (R796X) substitution, inherited from the unaffected father, and a c.5560G-A transition in exon 48, resulting in an asp1854-to-asn (D1854N; 600286.0002) substitution at a highly conserved residue in the kinase-binding domain, inherited from the unaffected mother. The mutations, which were found by a combination of exome sequencing and linkage analysis, were confirmed by Sanger sequencing. Neither mutation was found in 274 in-house genomes of mixed ancestry or in 500 Dutch genomes, but both were detected once in the ExAC database. Parental blood samples detected both mutations at the RNA level. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The fetuses were electively terminated between 16 and 34 weeks' gestation. </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 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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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PI4KA, ASP1854ASN
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<br />
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SNP: rs747119727,
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gnomAD: rs747119727,
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ClinVar: RCV000190466, RCV001311593
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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>For discussion of the c.5560G-A transition (c.5560G-A, NM_058004.3) in the PI4KA gene, resulting in an asp1854-to-asn (D1854N) substitution, that was found in compound heterozygous state in tissue samples from 3 fetuses with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see 616531) by Pagnamenta et al. (2015), see 600286.0001. </p><p>In a 5-year-old boy (patient 8), born of consanguineous Turkish parents, with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified a homozygous D1854N substitution in the PI4KA gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed. The patient had spastic tetraparesis, severe developmental delay, and polymicrogyria. </p><p>In a 13-year-old girl (P3), born of consanguineous Turkish parents, with NEDSPLB, Salter et al. (2021) identified a homozygous D1854N mutation in the PI4KA gene that segregated with the disorder in the family. Functional studies of the variant were not performed. The patient presented on the first day of life with refractory seizures and later showed severe global developmental delay, central hypotonia, peripheral spasticity, hypomyelinating leukodystrophy, immunodeficiency, and suspected inflammatory bowel disease. </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 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</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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PI4KA, 1-BP DUP, 2624C
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<br />
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SNP: rs747391554,
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gnomAD: rs747391554,
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ClinVar: RCV001785408
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 4-year-old girl (patient 1) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a 1-bp duplication (c.2624dupC) in exon 22, resulting in a frameshift and premature termination (Pro876SerfsTer36), and a c.3454G-A transition in exon 30, resulting in a glu1152-to-lys (E1152K; 600286.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.2624dupC mutation was found once in the gnomAD v2.1.1 database (1 of 250,576 alleles). The E1154K mutation was found once in the gnomAD v2.1.1 database (1 of 251,262 alleles). In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. </p>
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</span>
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</div>
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<div>
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|
<br />
|
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</div>
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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PI4KA, GLU1152LYS
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|
<br />
|
|
|
|
SNP: rs1351749039,
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|
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|
|
gnomAD: rs1351749039,
|
|
|
|
|
|
ClinVar: RCV001785409, RCV002074080
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the c.3454G-A transition in the PI4KA gene, resulting in a glu1152-to-lys (E1152K; 600286.0004) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Verdura et al. (2021), see 600286.0003. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
|
|
</div>
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</div>
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|
<div>
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|
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
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|
PI4KA, ALA1198THR
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|
<br />
|
|
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|
SNP: rs1929601378,
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|
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|
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|
|
ClinVar: RCV001785410
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
|
|
<p>In a 19-year-old woman (patient 4) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a c.3592G-A transition in exon 31, resulting in an ala1198to-thr (A1198T) substitution at a conserved residue, and a 4-bp deletion in exon 53 (c.6156_6159delGACA; 600286.0006), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD v2.1.1 database. Western blot analysis of patient cells showed decreased protein levels compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
SPASTIC PARAPLEGIA 84, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, 4-BP DEL, 6156GACA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs139598272,
|
|
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|
|
|
gnomAD: rs139598272,
|
|
|
|
|
|
ClinVar: RCV001785411, RCV001785412, RCV002541233
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Verdura et al. (2021), see 600286.0003. </p><p>For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; 619621), see 600286.0007.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPASTIC PARAPLEGIA 84, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, 3-BP DEL, 5459AAG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1925715512,
|
|
|
|
|
|
|
|
ClinVar: RCV001785413
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-year-old man (patient 9) with autosomal recessive spastic paraplegia-84 (SPG84; 619621), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a 3-bp deletion (c.5459_5461delAAG) in exon 47, resulting in an in-frame deletion of conserved residue (Glu1820del, E1820del), and a 4-bp deletion (c.6156_6159delGACA; 600286.0006), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The Glu1820del mutation was not present in gnomAD v2.1.1, but was found in 1 of 143,164 alleles in v3. The c.6156_6159delGACA was not present in the gnomAD database. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPASTIC PARAPLEGIA 84, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, VAL1556MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs144363917,
|
|
|
|
|
|
gnomAD: rs144363917,
|
|
|
|
|
|
ClinVar: RCV001785414, RCV003479351, RCV004591566
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-year-old man of Hispanic descent (patient 10), with autosomal recessive spastic paraplegia-84 (SPG84; 619621) Verdura et al. (2021) identified compound heterozygous missense mutations in the PI4KA gene: a c.4666G-A transition in exon 39, resulting in a val1556-to-met (V1556M) substitution, and a c.5159C-T transition in exon 44, resulting in a thr1720-to-ile (T1720I; 600286.0009). Both mutations occurred at conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARAPLEGIA 84, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, THR1720ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147194890,
|
|
|
|
|
|
|
|
ClinVar: RCV001785415
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.5159C-T transition in the PI4KA gene, resulting in a thr1720-to-ile (T1720I) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; 619621) by Verdura et al. (2021), see 600286.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 GASTROINTESTINAL DEFECTS AND IMMUNODEFICIENCY SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, TYR1623ASP ({dbSNP rs776650691})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs776650691,
|
|
|
|
|
|
gnomAD: rs776650691,
|
|
|
|
|
|
ClinVar: RCV001822068
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; 619708), Salter et al. (2021) identified a homozygous c.4867T-G transversion (c.4867T-G, NM_058004.3) in the PI4KA gene, resulting in a tyr1623-to-asp (Y1623D) substitution at a conserved residue distal from the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the heterozygous state only in the gnomAD database (8.0 x 10(-6)). In vitro studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (609332), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; 243150). All infants died in the first weeks of life; 2 patients had evidence of an immunodeficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, GLY1925GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147171210,
|
|
|
|
|
|
|
|
ClinVar: RCV001822069
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl (family 4) of Indian descent with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Salter et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a c.5774G-A transition (c.5774G-A, NM_058004.3), resulting in a gly1925-to-glu (G1925E) substitution at a conserved residue in the catalytic domain, and a 1-bp deletion (c.6065delG; 600286.0012) in exon 52, predicted to result in a frameshift and premature termination (Arg2022GlnfsTer36). The mutations, which were found by trio-based whole-genome sequencing, segregated with the disorder in the family. Both were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. The patient had developmental delay, spasticity, leukoencephalopathy, colitis, and autoimmune enteropathy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, 1-BP DEL, 6065G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1419816068,
|
|
|
|
|
|
gnomAD: rs1419816068,
|
|
|
|
|
|
ClinVar: RCV001822070
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.6065delG, NM_058004.3) in exon 52 of the PI4KA gene, resulting in a frameshift and premature termination (Arg2022GlnfsTer36), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Salter et al. (2021), see 600286.0011. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, LEU777PRO ({dbSNP rs1490645147})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1490645147,
|
|
|
|
|
|
gnomAD: rs1490645147,
|
|
|
|
|
|
ClinVar: RCV001822071
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old German woman (family 7) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Salter et al. (2021)m identified compound heterozygous mutations in the PI4KA gene: a c.2330T-C transition (c.2330T-C, NM_058004.3), resulting in a leu777-to-pro (L777P) substitution, and a c.3571C-T transition in exon 31, resulting in a gln1191-to-ter (Q1191X; 600286.0014) substitution. L777P was found at a low frequency in the heterozygous state in the gnomAD database (4 x 10(-6)), whereas Q1191X was not found in gnomAD. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but molecular modeling predicted that they would interfere with PI4KA function. The patient had global developmental delay, seizures, spasticity, and leukoencephalopathy. She did not have gastrointestinal disease or immunodeficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, HYPOMYELINATING LEUKODYSTROPHY, AND BRAIN ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PI4KA, GLN1191TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147287553,
|
|
|
|
|
|
|
|
ClinVar: RCV001822072
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.3571C-T transition (c.3571C-T, NM_058004.3) in exon 31, resulting in a gln1191-to-ter (Q1191X) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Salter et al. (2021), see 600286.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., Messa, M., Baldassari, S., Assereto, S., Biancheri, R., Zara, F., Minetti, C., Raimondi, A., Simons, M., Walther, T. C., Reinisch, K. M., De Camilli, P.
|
|
<strong>The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane.</strong>
|
|
Nat. Cell Biol. 18: 132-138, 2016.
|
|
|
|
|
|
[PubMed: 26571211]
|
|
|
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Bao Lige - updated : 08/07/2023<br>Cassandra L. Kniffin - updated : 01/18/2022<br>Cassandra L. Kniffin - updated : 11/17/2021<br>Matthew B. Gross - updated : 1/29/2016<br>Patricia A. Hartz - updated : 1/14/2016<br>Cassandra L. Kniffin - updated : 8/24/2015<br>Ada Hamosh - updated : 8/29/2012<br>Patti M. Sherman - updated : 6/30/1998
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Victor A. McKusick : 1/6/1995
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