5569 lines
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Entry
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- *601255 - KINESIN FAMILY MEMBER 1A; KIF1A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601255</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601255">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000130294;t=ENST00000498729" 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=547" 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=601255" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000130294;t=ENST00000498729" 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_001244008,NM_001320705,NM_001330289,NM_001330290,NM_001379631,NM_001379632,NM_001379633,NM_001379634,NM_001379635,NM_001379636,NM_001379637,NM_001379638,NM_001379639,NM_001379640,NM_001379641,NM_001379642,NM_001379645,NM_001379646,NM_001379648,NM_001379649,NM_001379650,NM_001379651,NM_001379653,NM_004321,XM_047444818,XM_047444819,XM_047444820,XM_047444821" 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_001244008" 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=601255" 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=03156&isoform_id=03156_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/KIF1A" 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/1049291,1449006,2795892,4106715,19924175,40674643,52545904,62087856,62702314,62702315,68533113,84627460,84627478,119364606,119591620,119591621,119591622,119591623,166788556,344179050,345842524,608785355,608785357,608785595,608785712,1002623487,1057866198,1057866897,1827520732,1829778828,1829778841,1829778847,1829778857,1829778877,1829778881,1829778883,1829778902,1829778910,1829778927,1829778934,1829778971,1829778979,1829778985,1829778993,1829779011,1829779018,1829779020,1829779035,2217329011,2217329013,2217329015,2217329017,2462574510,2462574512,2462574514,2462574516,2462574518" 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/Q12756" 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=547" 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=ENSG00000130294;t=ENST00000498729" 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=KIF1A" 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=KIF1A" 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+547" 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/KIF1A" 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:547" 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/547" 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=chr2&hgg_gene=ENST00000498729.9&hgg_start=240713767&hgg_end=240821403&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:888" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:888" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601255[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601255[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KIF1A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000130294" 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=KIF1A" 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=KIF1A" 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=KIF1A" 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=KIF1A&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/PA25180" 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:888" 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/FBgn0267002.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:108391" 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/KIF1A#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:108391" 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/547/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=547" 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=WBGene00006831;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-070912-480" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:601255" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:547" 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=KIF1A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 763377006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601255
|
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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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KINESIN FAMILY MEMBER 1A; KIF1A
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
AXONAL TRANSPORTER OF SYNAPTIC VESICLES; ATSV<br />
|
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UNC104, C. ELEGANS, HOMOLOG OF; UNC104<br />
|
|
KINESIN, HEAVY CHAIN, MEMBER 1A, MOUSE, HOMOLOG OF
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KIF1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KIF1A</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/2/1177?start=-3&limit=10&highlight=1177">2q37.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:240713767-240821403&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'})">2:240,713,767-240,821,403</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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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>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614255,614213,610357,620607" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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2q37.3
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<a href="/entry/614255"> 614255 </a>
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Neuropathy, hereditary sensory, type IIC
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<a href="/entry/614213"> 614213 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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Spastic paraplegia 30, autosomal dominant
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<a href="/entry/610357"> 610357 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Spastic paraplegia 30, autosomal recessive
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<a href="/entry/620607"> 620607 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/601255" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601255" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The KIF1A gene encodes a motor protein involved in the anterograde transport of synaptic-vesicle (SV) precursors along axons (summary by <a href="#24" class="mim-tip-reference" title="Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others. <strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong> Am. J. Hum. Genet. 89: 219-230, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820098">Riviere et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a search for candidate genes for the tuberous sclerosis-1 (TSC1; <a href="/entry/191100">191100</a>) disease locus, <a href="#5" class="mim-tip-reference" title="Furlong, R. A., Zhou, C. Y., Ferguson-Smith, M. A., Affara, N. A. <strong>Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9q34.</strong> Genomics 33: 421-429, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661001</a>] [<a href="https://doi.org/10.1006/geno.1996.0217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661001">Furlong et al. (1996)</a> identified a novel gene, the axonal transporter of synaptic vesicles (ATSV) gene, that maps adjacent to a CpG island, approximately 80 kb centromeric of the ABO (<a href="/entry/110300">110300</a>) locus on chromosome 9q34.1-q34.2. (The ATSV gene was later mapped to chromosome 2q37; see 'Mapping,' below.) <a href="#5" class="mim-tip-reference" title="Furlong, R. A., Zhou, C. Y., Ferguson-Smith, M. A., Affara, N. A. <strong>Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9q34.</strong> Genomics 33: 421-429, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661001</a>] [<a href="https://doi.org/10.1006/geno.1996.0217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661001">Furlong et al. (1996)</a> obtained 7 kb of continuous sequence from a series of overlapping cosmid clones and corresponding cDNA clones which were isolated from a brain cDNA library. Sequence analysis revealed an open reading frame of 5,070 bp encoding a putative protein which shows 97% identity at the amino acid level to the mouse KIF1A gene product and 42% identity with the C. elegans unc-104 genes. Both KIF1A and unc-104 function in the anterograde axonal transport of synaptic vesicles and are members of the kinesin gene family (see <a href="/entry/600025">600025</a>). The ATSV gene is transcribed in the direction 9qter to 9cen. A CpG island was found at the 3-prime end of the gene. The ATSV gene probes detected a NotI polymorphism which occurred with a frequency of 2%. <a href="#5" class="mim-tip-reference" title="Furlong, R. A., Zhou, C. Y., Ferguson-Smith, M. A., Affara, N. A. <strong>Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9q34.</strong> Genomics 33: 421-429, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661001</a>] [<a href="https://doi.org/10.1006/geno.1996.0217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661001">Furlong et al. (1996)</a> found no supporting evidence for ATSV as the candidate TSC1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#15" class="mim-tip-reference" title="Lawrence, C. J., Dawe, R. K., Christie, K. R., Cleveland, D. W., Dawson, S. C., Endow, S. A., Goldstein, L. S. B., Goodson, H. V., Hirokawa, N., Howard, J., Malmberg, R. L., McIntosh, J. R., and 10 others. <strong>A standardized kinesin nomenclature.</strong> J. Cell Biol. 167: 19-22, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479732</a>] [<a href="https://doi.org/10.1083/jcb.200408113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15479732">Lawrence et al. (2004)</a> presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF1A belongs to the kinesin-3 family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Kinesin-related proteins constitute a large superfamily of microtubule-dependent proteins that mediate specific and diverse motile processes, including intracellular transport and cell division. The human ATSV protein is a member of the kinesin family and shows 95% identity to the KIF1A protein of mouse (<a href="#21" class="mim-tip-reference" title="Okada, Y., Yamazaki, H., Sekine-Aizawa, Y., Hirokawa, N. <strong>The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors.</strong> Cell 81: 769-780, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7539720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7539720</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90538-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7539720">Okada et al., 1995</a>). KIF1A is an anterograde motor protein that transports membranous organelles along axonal microtubules. Its cargo includes a subset of precursors for synaptic vesicles: synaptophysin (<a href="/entry/313475">313475</a>), synaptotagmin (<a href="/entry/185605">185605</a>), and Rab3A (<a href="/entry/179490">179490</a>). The phenotype of KIF1A knockout mice includes motor and sensory disturbances, a reduction in the density of synaptic vesicles in nerve terminals, and accumulation of clear vesicles in nerve cell bodies (<a href="#31" class="mim-tip-reference" title="Yonekawa, Y., Harada, A., Okada, Y., Funakoshi, T., Kanai, Y., Takei, Y., Terada, S., Noda, T., Hirokawa, N. <strong>Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.</strong> J. Cell Biol. 141: 431-441, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9548721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9548721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9548721[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.141.2.431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9548721">Yonekawa et al., 1998</a>). It can be hypothesized that ATSV (and KIF1A in the mouse) may play a critical role in the development of axonal neuropathies resulting from impaired axonal transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7539720+9548721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an in vitro motility assay, <a href="#13" class="mim-tip-reference" title="Klopfenstein, D. R., Tomishige, M., Stuurman, N., Vale, R. D. <strong>Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor.</strong> Cell 109: 347-358, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015984</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12015984[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00708-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015984">Klopfenstein et al. (2002)</a> showed that Dictyostelium Unc104 uses a lipid-binding pleckstrin homology (PH) domain to dock onto membrane cargo. Through its PH domain, Unc104 could transport phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2)-containing liposomes with similar properties to native vesicles. Liposome movement by monomeric Unc104 motors showed a steep dependence on PtdIns(4,5)P2 concentration, even though liposome binding was noncooperative. This switch-like transition for movement could be shifted to lower PtdIns(4,5)P2 concentrations by the addition of cholesterol/sphingomyelin or GM1 ganglioside/cholera toxin, conditions that produced raft-like behavior of Unc104 bound to lipid bilayers. The authors concluded that clustering of Unc104 in PtdIns(4,5)P2-containing rafts provides a trigger for membrane transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12015984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tomishige, M., Klopfenstein, D. R., Vale, R. D. <strong>Conversion of Unc104/KIF1A kinesin into a processive motor after dimerization.</strong> Science 297: 2263-2267, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12351789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12351789</a>] [<a href="https://doi.org/10.1126/science.1073386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12351789">Tomishige et al. (2002)</a> demonstrated that KIF1A can dimerize and move unidirectionally and processively with rapid velocities characteristic of transport in living cells. Their results suggested that KIF1A operates in vivo by a mechanism similar to conventional kinesin and that regulation of motor dimerization may be used to control transport by this class of kinesins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12351789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 yeast 2-hybrid screen using a human fetal brain cDNA library, <a href="#24" class="mim-tip-reference" title="Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others. <strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong> Am. J. Hum. Genet. 89: 219-230, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820098">Riviere et al. (2011)</a> found that the KIF1A gene interacted with the HSN2 exon of WNK1 (<a href="/entry/605232">605232</a>). Immunoprecipitation studies showed that the 2 proteins localized in cultured primary sensory neurons prepared from adult mouse dorsal root ganglia. Both proteins were found to localize in cell bodies and along axons, suggesting a role in axonal transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a mass spectrometry approach, <a href="#27" class="mim-tip-reference" title="Stucchi, R., Plucinska, G., Hummel, J. J. A., Zahavi, E. E., Guerra San Juan, I., Klykov, O., Scheltema, R. A., Maarten Altelaar, A. F., Hoogenraad, C. C. <strong>Regulation of KIF1A-driven dense core vesicle transport: Ca(2+)/CaM controls DCV binding and liprin-alpha/TANC2 recruits DCVs to postsynaptic sites.</strong> Cell Rep. 24: 685-700, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30021165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30021165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30021165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.celrep.2018.06.071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30021165">Stucchi et al. (2018)</a> identified TANC2 (<a href="/entry/615047">615047</a>), liprin-alpha-2 (PPFIA2; <a href="/entry/603143">603143</a>), and the calcium-binding protein calmodulin (see CALM1, <a href="/entry/114180">114180</a>) as direct binding partners of KIF1A, the primary motor protein for SVs and dense core vesicles (DCVs). Analysis with rat hippocampal neurons revealed that calcium enhanced Kif1a binding to DCVs and increased vesicle motility by acting through calmodulin. Tanc2 and liprin-alpha-2 were enriched in dendritic spines but were not part of the Kif1a cargo complex. Instead, they acted as postsynaptic density scaffolds to stop and capture Kif1a-bound DCVs upon dendritic spine entry. Knockdown experiments showed that depletion of Tanc2, Kif1a, or liprin-alpha-2 affected rat dendritic spine density and morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30021165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>X-Ray Crystallography and Cryoelectron Microscopy</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Kikkawa, M., Okada, Y., Hirokawa, N. <strong>15-angstrom resolution model of the monomeric kinesin motor, KIF1A.</strong> Cell 100: 241-252, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10660047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10660047</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81562-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10660047">Kikkawa et al. (2000)</a> generated a 15-angstrom resolution map of the KIF1A-microtubule complex, which allowed clear visualization of the K loop, a 12-amino acid insert in the L12 region, as an arm-like structure. Furthermore, this high-resolution model revealed how kinesin motors interact with microtubules. KIF1A has 3 microtubule-binding sites, termed MB1, MB2, and MB3. MB3 is the unique arm-like projection containing the K loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10660047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#10" class="mim-tip-reference" title="Kikkawa, M., Sablin, E. P., Okada, Y., Yajima, H., Fletterick, R. J., Hirokawa, N. <strong>Switch-based mechanism of kinesin motors.</strong> Nature 411: 439-445, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11373668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11373668</a>] [<a href="https://doi.org/10.1038/35078000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11373668">Kikkawa et al. (2001)</a> studied the monomeric kinesin motor KIF1A using x-ray crystallography and cryoelectron microscopy, to allow analysis of force-generating conformational changes at atomic resolution. Their analysis revealed the motor in its 2 functionally critical states, complexed with ADP and with a nonhydrolyzable analog of ATP. The conformational change observed between the 2 structures of the KIF1A catalytic core is modular, extends to all kinesins, and is similar to the conformational change used by myosin motors and G proteins. Docking of the ADP-bound and ATP-like crystallographic models of KIF1A into the corresponding cryoelectron microscopy maps suggests a rationale for the plus-end directional bias associated with the kinesin catalytic core. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11373668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Nitta, R., Kikkawa, M., Okada, Y., Hirokawa, N. <strong>KIF1A alternately uses two loops to bind microtubules.</strong> Science 305: 678-683, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15286375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15286375</a>] [<a href="https://doi.org/10.1126/science.1096621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15286375">Nitta et al. (2004)</a> reported crystal structures of monomeric kinesin KIF1A with 3 transition-state analogs: adenylyl imidodiphosphate (AMP-PNP), adenosine diphosphate (ADP)-vanadate, and ADP-AlFx (aluminofluoride complexes). These structures, together with known structures of the ADP-bound state and the adenylyl-(beta,gamma-methylene) diphosphate (AMP-PCP)-bound state, show that kinesin uses 2 microtubule-binding loops in an alternating manner to change its interaction with microtubules during the ATP hydrolysis cycle; loop L11 is extended into the AMP-PNP structure, whereas loop L12 is extended in the ADP structure. ADP-vanadate displays an intermediate structure in which a conformational change in 2 switch regions causes both loops to be raised from the microtubule, thus actively detaching kinesin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15286375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Optical Trapping</em></strong></p><p>
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By measuring its movement with an optical trapping system, <a href="#20" class="mim-tip-reference" title="Okada, Y., Higuchi, H., Hirokawa, N. <strong>Processivity of the single-headed kinesin KIF1A through biased binding to tubulin.</strong> Nature 424: 574-577, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12891363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12891363</a>] [<a href="https://doi.org/10.1038/nature01804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12891363">Okada et al. (2003)</a> used KIF1A as a model molecule to demonstrate that a single ATP hydrolysis triggers a single stepping movement of a single KIF1A monomer. The step size is distributed stochastically around multiples of 8 nm with a gaussian-like envelope and a standard deviation of 15 nm. On average, the step is directional to the microtubule's plus-end against a load force of up to 0.15 pN. As the source for this directional movement, <a href="#20" class="mim-tip-reference" title="Okada, Y., Higuchi, H., Hirokawa, N. <strong>Processivity of the single-headed kinesin KIF1A through biased binding to tubulin.</strong> Nature 424: 574-577, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12891363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12891363</a>] [<a href="https://doi.org/10.1038/nature01804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12891363">Okada et al. (2003)</a> showed that KIF1A moves to the microtubule's plus-end by approximately 3 nm on average on binding to the microtubule, presumably by preferential binding to tubulin on the plus-end side. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12891363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Amyotrophic lateral sclerosis-4 (ALS4; <a href="/entry/602433">602433</a>) is an autosomal dominant, juvenile-onset motor systems disease with an axonal phenotype that includes prominent axonal swelling. The ALS4 locus maps to 9q34, a region that overlaps the putative ATSV gene region, making it an attractive positional and functional candidate gene for ALS4. <a href="#8" class="mim-tip-reference" title="Keller, M. P., Seifried, B. A., Rabin, B. A., Chance, P. F. <strong>Mapping of the kinesin-related gene ATSV to chromosome 2q37.</strong> Hum. Genet. 104: 254-256, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323250</a>] [<a href="https://doi.org/10.1007/s004390050944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323250">Keller et al. (1999)</a> investigated the ATSV gene as a candidate gene for ALS4 and failed to confirm the assignment of the ATSV gene to chromosome 9. By PCR analysis of a human/rodent somatic cell hybrid panel and by FISH, they instead mapped the human ATSV gene to 2q37. The ATSV gene therefore becomes a candidate gene for other peripheral nerve disorders involving altered axonal transport mapping to 2q37. <a href="#8" class="mim-tip-reference" title="Keller, M. P., Seifried, B. A., Rabin, B. A., Chance, P. F. <strong>Mapping of the kinesin-related gene ATSV to chromosome 2q37.</strong> Hum. Genet. 104: 254-256, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323250</a>] [<a href="https://doi.org/10.1007/s004390050944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323250">Keller et al. (1999)</a> suggested that a limited stretch of sequence identity to the ATSV transcript in the previously identified region of 9q34 may have led to the prior conclusion that the ATSV gene maps to chromosome 9. Alternatively, a chimerism in the YAC clone used to generate the cosmid in that previous study may have led to the erroneous mapping of the ATSV gene to 9q34. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spastic Paraplegia 30A, Autosomal Dominant</em></strong></p><p>
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In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; <a href="/entry/610357">610357</a>), <a href="#30" class="mim-tip-reference" title="Ylikallio, E., Kim, D., Isohanni, P., Auranen, M., Kim, E., Lonnqvist, T., Tyynismaa, H. <strong>Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.</strong> Europ. J. Hum. Genet. 23: 1427-1430, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25585697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25585697</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25585697[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/ejhg.2014.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25585697">Ylikallio et al. (2015)</a> identified a heterozygous mutation (S69L; <a href="#0014">601255.0014</a>) in the KIF1A gene; the substitution affected a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25585697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30A, <a href="#2" class="mim-tip-reference" title="Citterio, A., Arnoldi, A., Panzeri, E., Merlini, L., D'Angelo, M. G., Musumeci, O., Toscano, A., Bondi, A., Martinuzzi, A., Bresolin, N., Bassi, M. T. <strong>Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.</strong> J. Neurol. 262: 2684-2690, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26410750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26410750</a>] [<a href="https://doi.org/10.1007/s00415-015-7899-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26410750">Citterio et al. (2015)</a> identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26410750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 members of a 3-generational family with SPG30, <a href="#25" class="mim-tip-reference" title="Roda, R. H., Schindler, A. B., Blackstone, C. <strong>Multigeneration family with dominant SPG30 hereditary spastic paraplegia.</strong> Ann. Clin. Transl. Neurol. 4: 821-824, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29159194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29159194</a>] [<a href="https://doi.org/10.1002/acn3.452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29159194">Roda et al. (2017)</a> identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29159194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 patients (patients 6, 8A, 8B, and 9), including 2 sibs, with SPG30A, <a href="#17" class="mim-tip-reference" title="Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. <strong>KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement.</strong> J. Peripher. Nerv. Syst. 25: 117-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32096284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32096284</a>] [<a href="https://doi.org/10.1111/jns.12368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32096284">Nemani et al. (2020)</a> identified heterozygous mutations in the KIF1A gene. Three patients carried the S69L mutation, whereas 1 had an R11Q mutation. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 23 probands with SPG30A, <a href="#23" class="mim-tip-reference" title="Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. <strong>KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.</strong> Europ. J. Hum. Genet. 28: 40-49, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31488895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31488895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31488895[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/s41431-019-0497-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31488895">Pennings et al. (2020)</a> identified 19 different heterozygous point mutations in the KIF1A gene. There were 11 missense variants in the motor domain (see, e.g., S69L, <a href="#0014">601255.0014</a>), as well as 9 variants outside of the motor domain. Six of these 9 mutations were nonsense or frameshift mutations (see, e.g., <a href="#0015">601255.0015</a> and <a href="#0016">601255.0016</a>) predicted to result in a loss of function. Three variants were considered to be 'variants of unknown significance'. Functional studies of the variants and studies of patient cells were not performed. The findings suggested that autosomal dominant SPG30 can be caused by either missense or loss-of-function mutations. The patients were ascertained from a cohort of 347 probands with SPG who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31488895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spastic Paraplegia 30B, Autosomal Recessive</em></strong></p><p>
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By homozygosity mapping, exome sequencing, and examination of candidate genes, <a href="#3" class="mim-tip-reference" title="Erlich, Y., Edvardson, S., Hodges, E., Zenvirt, S., Thekkat, P., Shaag, A., Dor, T., Hannon, G. J., Elpeleg, O. <strong>Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.</strong> Genome Res. 21: 658-664, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21487076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21487076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21487076[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/10.1101/gr.117143.110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21487076">Erlich et al. (2011)</a> identified a homozygous mutation in the KIF1A gene (A255V; <a href="#0001">601255.0001</a>) in 3 Palestinian sibs with autosomal recessive spastic paraplegia-30B (SPG30B; <a href="/entry/620607">620607</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21487076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others. <strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong> Europ. J. Hum. Genet. 20: 645-649, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258533</a>] [<a href="https://doi.org/10.1038/ejhg.2011.261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22258533">Klebe et al. (2012)</a> identified a homozygous mutation in the KIF1A gene (R350G; <a href="#0005">601255.0005</a>) in affected members of a consanguineous Algerian family with SPG30B originally reported by <a href="#11" class="mim-tip-reference" title="Klebe, S., Azzedine, H., Durr, A., Bastien, P., Bouslam, N., Elleuch, N., Forlani, S., Charon, C., Koenig, M., Melki, J., Brice, A., Stevanin, G. <strong>Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.</strong> Brain 129: 1456-1462, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16434418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16434418</a>] [<a href="https://doi.org/10.1093/brain/awl012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16434418">Klebe et al. (2006)</a>. Another Palestinian family with the disorder was found to be homozygous for the A255V mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22258533+16434418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Functional Studies of SPG30-Associated KIF1A Mutations</em></strong></p><p>
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Using in vitro motility assays and rescue experiments in C. elegans, <a href="#1" class="mim-tip-reference" title="Chiba, K., Takahashi, H., Chen, M., Obinata, H., Arai, S., Hashimoto, K., Oda, T., McKenney, R. J., Niwa, S. <strong>Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.</strong> Proc. Nat. Acad. Sci. 116: 18429-18434, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31455732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31455732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31455732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1905690116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31455732">Chiba et al. (2019)</a> showed that some SPG30-associated mutations in human KIF1A, including A255V and R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutations in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. The authors concluded that hyperactivation of kinesin motor activity can cause motor neuron disease in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31455732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Hereditary Sensory Neuropathy, Type IIC</em></strong></p><p>
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By genomewide homozygosity mapping followed by candidate gene analysis in a consanguineous Afghan family with hereditary sensory neuropathy type IIC (HSN2C; <a href="/entry/614213">614213</a>), <a href="#24" class="mim-tip-reference" title="Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others. <strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong> Am. J. Hum. Genet. 89: 219-230, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820098">Riviere et al. (2011)</a> identified a homozygous truncating mutation in the KIF1A gene (<a href="#0002">601255.0002</a>). Screening of this gene in 112 unrelated patients with HSN identified 2 additional families with the same mutation and 1 patient who was compound heterozygous for 2 mutations (<a href="#0002">601255.0002</a> and <a href="#0003">601255.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>NESCAV Syndrome</em></strong></p><p>
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In a patient with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#6" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a> identified a missense mutation (T99M; <a href="#0004">601255.0004</a>) in the KIF1A gene. The mutation affected localization of the KIF1A protein in neurites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21376300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 14 patients, including a pair of monozygotic twins, with NESCAVS, <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> identified 11 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., <a href="#0004">601255.0004</a>, <a href="#0006">601255.0006</a>-<a href="#0008">601255.0008</a>). The mutations in 12 families were found by exome sequencing; the mutation in 1 family was found by targeted next-generation sequencing. All the mutations occurred at conserved residues in the motor domain. In vitro functional expression studies of 5 of the mutations in rat hippocampal cells showed that they resulted in greatly reduced distal localization in neurites compared to wildtype. The patients had intellectual disability with variable cerebellar atrophy, spastic paraparesis, optic atrophy, peripheral neuropathy, and seizures. <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> hypothesized that, since KIF1A functions as an active dimer, heterozygous missense mutations may exert a dominant-negative effect, which may explain the severe phenotype compared to those with recessive mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 with NESCAVS, <a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., <a href="#0004">601255.0004</a>, <a href="#0007">601255.0007</a>, <a href="#0009">601255.0009</a>-<a href="#0010">601255.0010</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred at conserved residues in the motor domain, and in vitro functional microtubule gliding assays of several of the mutations showed that they resulted in a loss of motility with evidence for a dominant-negative effect. The patients had a severe neurodegenerative encephalopathy, with progressive cerebral and cerebellar atrophy, thus expanding the phenotype associated with de novo KIF1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5 unrelated patients with NESCAVS, <a href="#19" class="mim-tip-reference" title="Ohba, C., Haginoya, K., Osaka, H., Kubota, K., Ishiyama, A., Hiraide, T., Komaki, H., Sasaki, M., Miyatake, S., Nakashima, M., Tsurusaki, Y., Miyake, N., Tanaka, F., Saitsu, H., Matsumoto, N. <strong>De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.</strong> J. Hum. Genet. 60: 739-742, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26354034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26354034</a>] [<a href="https://doi.org/10.1038/jhg.2015.108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26354034">Ohba et al. (2015)</a> identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., <a href="#0011">601255.0011</a> and <a href="#0012">601255.0012</a>). All of the mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, affected highly conserved residues in the motor domain. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that the variants would destabilize the protein or affect protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26354034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 unrelated patients with NESCAVS, <a href="#7" class="mim-tip-reference" title="Hotchkiss, L., Donkervoort, S., Leach, M. E., Mohassel, P., Bharucha-Goebel, D. X., Bradley, N., Nguyen, D., Hu, Y., Gurgel-Giannetti, J., Bonnemann, C. G. <strong>Novel de novo mutations in KIF1A as a cause of hereditary spastic paraplegia with progressive central nervous system involvement.</strong> J. Child Neurol. 31: 1114-1119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27034427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27034427</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27034427[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/10.1177/0883073816639718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27034427">Hotchkiss et al. (2016)</a> identified 2 de novo heterozygous missense mutations in the KIF1A gene (see, e.g., G199R, <a href="#0013">601255.0013</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variants and studies of patient cells were not performed, but both occurred in the motor domain and were predicted to interfere with microtubule binding, possibly with a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27034427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 unrelated patients with NESCAVS, <a href="#29" class="mim-tip-reference" title="Van Beusichem, A. E., Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M. A., Kamsteeg, E. J., Stumpel, C., Vermeulen, R. J. <strong>Mobility characteristics of children with spastic paraplegia due to a mutation in the KIF1A gene.</strong> Neuropediatrics 51: 146-153, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31805580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31805580</a>] [<a href="https://doi.org/10.1055/s-0039-3400988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31805580">Van Beusichem et al. (2020)</a> identified de novo heterozygous missense variants in the KIF1A gene (R380W; R216C, <a href="#0009">601255.0009</a>). Functional studies of the variants and studies of patient cells were not performed. In a review of previously reported cases, the authors concluded that there is no apparent genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31805580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, <a href="#26" class="mim-tip-reference" title="Samanta, D., Gokden, M. <strong>PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex.</strong> J. Clin. Neurosci. 61: 298-301, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30385166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30385166</a>] [<a href="https://doi.org/10.1016/j.jocn.2018.10.091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30385166">Samanta and Gokden (2019)</a> identified a de novo heterozygous E253K mutation in the KIF1A gene (<a href="#0007">601255.0007</a>). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30385166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 patients with NESCAVS, <a href="#17" class="mim-tip-reference" title="Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. <strong>KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement.</strong> J. Peripher. Nerv. Syst. 25: 117-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32096284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32096284</a>] [<a href="https://doi.org/10.1111/jns.12368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32096284">Nemani et al. (2020)</a> identified de novo heterozygous mutations in the KIF1A gene (see, e.g., R254W, <a href="#0012">601255.0012</a> and R307P, <a href="#0017">601255.0017</a>). All except 1 were missense variants affecting the kinesin motor domain; 1 was a splice site mutation. Two patients with profound encephalopathy carried the heterozygous E253K mutation. 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<p><a href="#12" class="mim-tip-reference" title="Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others. <strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong> Europ. J. Hum. Genet. 20: 645-649, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258533</a>] [<a href="https://doi.org/10.1038/ejhg.2011.261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22258533">Klebe et al. (2012)</a> observed that patients with truncating mutations in the KIF1A gene (see, e.g., <a href="#0002">601255.0002</a>) tended to present with a peripheral nervous system disorder (HSN2C), whereas those with missense mutations (see, e.g., <a href="#0001">601255.0001</a>) tended to present with an upper motor neuron syndrome of the central nervous system (SPG30). However, some patients with central nervous system spasticity also developed dysfunction of the peripheral nervous system, and only a few families with KIF1A mutations had been reported by that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22258533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" class="mim-tip-reference" title="Yonekawa, Y., Harada, A., Okada, Y., Funakoshi, T., Kanai, Y., Takei, Y., Terada, S., Noda, T., Hirokawa, N. <strong>Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.</strong> J. Cell Biol. 141: 431-441, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9548721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9548721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9548721[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.141.2.431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9548721">Yonekawa et al. (1998)</a> found that Kif1a-null mice died within several days after birth and showed severe motor and sensory disturbances, including ataxia, abnormal limb movements, and diminished pain response. Analysis of spinal cord cells and axons showed decreased densities of nerve terminals and synaptic vesicles in the nerve terminals and abnormal clustering of small vesicles in nerve cell bodies, suggesting a defect in anterograde axonal transport. Mutant mice also showed significant neuronal and axonal degeneration and death, and neuronal degeneration and death also occurred in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wildtype neurons or exposure to a low concentration of glutamate, suggesting that the neuronal death was due to lack of afferent stimulation resulting from lack of synaptic transmission. The findings indicated that Kif1a transports synaptic vesicle precursors and that this action plays a critical role in viability, maintenance, and function of neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9548721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 Palestinian sibs with autosomal recessive spastic paraplegia-30B (SPG30B; <a href="/entry/620607">620607</a>), <a href="#3" class="mim-tip-reference" title="Erlich, Y., Edvardson, S., Hodges, E., Zenvirt, S., Thekkat, P., Shaag, A., Dor, T., Hannon, G. J., Elpeleg, O. <strong>Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.</strong> Genome Res. 21: 658-664, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21487076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21487076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21487076[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/10.1101/gr.117143.110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21487076">Erlich et al. (2011)</a> identified a homozygous mutation in the KIF1A gene, resulting in an ala255-to-val (A255V) substitution in a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was found in 3 of 573 individuals from the same ethnic origin, yielding a carrier frequency of 1:191 in this population. The patients had early childhood onset of pure spasticity and hyperreflexia affecting the lower limbs; sensation was intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21487076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others. <strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong> Europ. J. Hum. Genet. 20: 645-649, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258533</a>] [<a href="https://doi.org/10.1038/ejhg.2011.261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22258533">Klebe et al. (2012)</a> identified a homozygous A255V mutation in affected members of a consanguineous Palestinian family with SPG30B. Age at onset ranged from 10 to 39 years, and patients had spastic gait with axonal sensorineuropathy after long disease duration. None had cerebellar signs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22258533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rat hippocampal neurons, <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> found that the A255V mutation resulted in mildly decreased distal localization in neurites (80.8% compared to wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an in vitro microtubule gliding assay, <a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> showed that the mutant A255V protein had motility similar to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in vitro motility assays and rescue experiments in C. elegans, <a href="#1" class="mim-tip-reference" title="Chiba, K., Takahashi, H., Chen, M., Obinata, H., Arai, S., Hashimoto, K., Oda, T., McKenney, R. J., Niwa, S. <strong>Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.</strong> Proc. Nat. Acad. Sci. 116: 18429-18434, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31455732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31455732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31455732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1905690116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31455732">Chiba et al. (2019)</a> showed that some SPG30-associated mutations in human KIF1A, including A255V, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31455732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs587778791 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587778791;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/rs587778791?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=rs587778791" 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=rs587778791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 3 unrelated families with hereditary sensory neuropathy IIC (HSN2C; <a href="/entry/614213">614213</a>), <a href="#24" class="mim-tip-reference" title="Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others. <strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong> Am. J. Hum. Genet. 89: 219-230, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820098">Riviere et al. (2011)</a> identified a homozygous 1-bp deletion (2840delT) in the alternatively spliced exon 25b of the KIF1A gene, predicted to cause a frameshift (Leu947Argfs*4). The mutation was not found in 665 European controls. One of the families was Afghan, 1 was Turkish, and 1 was Belgian; 2 of the families were consanguineous. Another Belgian patient, with a more severe disorder, was compound heterozygous for 2840delT and a 1-bp insertion (5271dupC; <a href="#0003">601255.0003</a>) in exon 46, predicted to cause a frameshift and premature termination (Ser1758GlnfsTer7). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs587778798 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587778798;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=rs587778798" 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=rs587778798" 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=RCV000023086 OR RCV000056120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023086, RCV000056120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023086...</a>
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<p>For discussion of the 1-bp duplication in exon 46 of the KIF1A gene (5271dupC) that was found in compound heterozygous state in a patient with hereditary sensory neuropathy IIC (HSN2C; <a href="/entry/614213">614213</a>) by <a href="#24" class="mim-tip-reference" title="Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others. <strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong> Am. J. Hum. Genet. 89: 219-230, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820098">Riviere et al., 2011</a>, see <a href="#0002">601255.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NESCAV SYNDROME</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> rs387906799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906799;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/rs387906799?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=rs387906799" 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=rs387906799" 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=RCV000023087 OR RCV000207102 OR RCV000235916 OR RCV000690609 OR RCV004541014" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023087, RCV000207102, RCV000235916, RCV000690609, RCV004541014" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023087...</a>
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<p>In a 3.5-year-old girl (patient 7) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#6" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a> identified a heterozygous C-to-T transition at nucleotide 296 of the KIF1A gene, resulting in a thr-to-met substitution at codon 99 (T99M). The patient also had axial hypotonia with peripheral spasticity, and mild atrophy of the vermian region of the cerebellum on MRI. This mutation was not identified in the patient's parents or in 285 control chromosomes. Functional assays showed that the mutation affected the localization of KIF1A from distal regions of neurites, as seen in wildtype, to reduced distal localization and increased accumulation throughout the cell body and proximal neurites in cells transfected with a mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21376300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> identified a de novo heterozygous T99M mutation (c.296C-T, NM_001244008.1) in 2 unrelated girls (patients 1 and 2) with NESCAVS. The mutation occurred at a conserved residue in the nucleotide-binding pocket in the motor domain and was predicted to abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (15.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> identified a de novo heterozygous T99M mutation in 2 unrelated patients (patients 1 and 2) with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Okamoto, N., Miya, F., Tsunoda, T., Yanagihara, K., Kato, M., Saitoh, S., Yamasaki, M., Kanemura, Y., Kosai, K. <strong>KIF1A mutation in a patient with progressive neurodegeneration.</strong> J. Hum. Genet. 59: 639-641, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25253658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25253658</a>] [<a href="https://doi.org/10.1038/jhg.2014.80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25253658">Okamoto et al. (2014)</a> and <a href="#14" class="mim-tip-reference" title="Langlois, S., Tarailo-Graovac, M., Sayson, B., Drogemoller, B., Swenerton, A., Ross, C. J. D., Wasserman, W. W., van Karnebeek, C. D. M. <strong>De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.</strong> Europ. J. Hum. Genet. 24: 949-953, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26486474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26486474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26486474[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/ejhg.2015.217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26486474">Langlois et al. (2016)</a> identified de novo heterozygous T99M mutations in 2 unrelated patients with NESCAVS. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the findings further suggested that a severe phenotype is associated with this mutation. <a href="#22" class="mim-tip-reference" title="Okamoto, N., Miya, F., Tsunoda, T., Yanagihara, K., Kato, M., Saitoh, S., Yamasaki, M., Kanemura, Y., Kosai, K. <strong>KIF1A mutation in a patient with progressive neurodegeneration.</strong> J. Hum. Genet. 59: 639-641, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25253658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25253658</a>] [<a href="https://doi.org/10.1038/jhg.2014.80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25253658">Okamoto et al. (2014)</a> speculated that since the KIF1A protein homodimerizes, the T99M mutation may cause a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25253658+26486474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387907259 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907259;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=rs387907259" 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=rs387907259" 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=RCV000030681 OR RCV004584597" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030681, RCV004584597" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030681...</a>
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<p>In 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spastic paraplegia-30B (SPG30B; <a href="/entry/620607">620607</a>), who were originally reported by <a href="#11" class="mim-tip-reference" title="Klebe, S., Azzedine, H., Durr, A., Bastien, P., Bouslam, N., Elleuch, N., Forlani, S., Charon, C., Koenig, M., Melki, J., Brice, A., Stevanin, G. <strong>Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.</strong> Brain 129: 1456-1462, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16434418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16434418</a>] [<a href="https://doi.org/10.1093/brain/awl012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16434418">Klebe et al. (2006)</a>, <a href="#12" class="mim-tip-reference" title="Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others. <strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong> Europ. J. Hum. Genet. 20: 645-649, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258533</a>] [<a href="https://doi.org/10.1038/ejhg.2011.261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22258533">Klebe et al. (2012)</a> identified a homozygous 1048C-G transversion in exon 13 of the KIF1A gene, resulting in an arg350-to-gly (R350G) substitution at a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was not found in 970 control chromosomes. The mutation occurred at the end of the motor domain in close vicinity to the neck linker that has an important role in directionality. Affected individuals had spasticity, sensorimotor axonal neuropathy, and mild cerebellar signs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16434418+22258533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rat hippocampal neurons, <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> found that the R350G mutation resulted in greatly reduced distal localization in neurites (20.7% compared to wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in vitro motility assays and rescue experiments in C. elegans, <a href="#1" class="mim-tip-reference" title="Chiba, K., Takahashi, H., Chen, M., Obinata, H., Arai, S., Hashimoto, K., Oda, T., McKenney, R. J., Niwa, S. <strong>Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.</strong> Proc. Nat. Acad. Sci. 116: 18429-18434, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31455732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31455732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31455732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1905690116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31455732">Chiba et al. (2019)</a> showed that some SPG30-associated mutations in human KIF1A, including R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding human mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31455732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 4-year-old boy (patient 6) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> identified a de novo heterozygous c.643A-C transversion (c.643A-C, NM_001244008.1) in the KIF1A gene, resulting in a ser215-to-arg (S215R) substitution at a conserved residue in the nucleotide-binding pocket in the motor domain. Structural modeling predicted that the mutation would abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (13.5% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs672601369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601369;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=rs672601369" 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=rs672601369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated girls (patients 8 and 9) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> identified a de novo heterozygous c.757G-A transition (c.757G-A, NM_001244008.1) in the KIF1A gene, resulting in a glu253-to-lys (E253K) substitution at a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would disrupt this structure, suppress ATP gamma-phosphate release, and prevent additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (19.3% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. Both girls had a severe phenotype with optic atrophy and cerebral and cerebellar atrophy, resulting in death before age 4 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> identified a de novo heterozygous E253K mutation in a patient with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility and acted in a dominant-negative manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, <a href="#26" class="mim-tip-reference" title="Samanta, D., Gokden, M. <strong>PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex.</strong> J. Clin. Neurosci. 61: 298-301, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30385166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30385166</a>] [<a href="https://doi.org/10.1016/j.jocn.2018.10.091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30385166">Samanta and Gokden (2019)</a> identified a de novo heterozygous E253K mutation in the KIF1A gene. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30385166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. <strong>KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement.</strong> J. Peripher. Nerv. Syst. 25: 117-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32096284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32096284</a>] [<a href="https://doi.org/10.1111/jns.12368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32096284">Nemani et al. (2020)</a> identified de novo heterozygous E253K mutations in 2 unrelated infants (patients 1 and 2) with a severe form of NESCAV syndrome. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs672601366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601366;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=rs672601366" 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=rs672601366" 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 30-month-old girl (patient 5) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#16" class="mim-tip-reference" title="Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others. <strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong> Hum. Mutat. 36: 69-78, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25265257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25265257</a>] [<a href="https://doi.org/10.1002/humu.22709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25265257">Lee et al. (2015)</a> identified a de novo heterozygous c.604G-C transversion (c.604G-C, NM_001244008.1) in the KIF1A gene, resulting in an ala202-to-pro (A202P) substitution near a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would induce a conformational change, likely disrupting efficient ATP gamma-phosphate release and additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (9.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25265257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs797045164 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045164;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=rs797045164" 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=rs797045164" 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=RCV000191020 OR RCV000207243 OR RCV001255726 OR RCV001269905 OR RCV001389787 OR RCV001796966 OR RCV002514079" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191020, RCV000207243, RCV001255726, RCV001269905, RCV001389787, RCV001796966, RCV002514079" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191020...</a>
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<p>In a 2-year-old girl (patient 3) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> identified a de novo heterozygous c.646C-T transition (c.646C-T, NM_001244008) in the KIF1A gene, resulting in an arg216-to-cys (R216C) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. An in vitro microtubule gliding assay showed that the mutant protein had no motility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Van Beusichem, A. E., Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M. A., Kamsteeg, E. J., Stumpel, C., Vermeulen, R. J. <strong>Mobility characteristics of children with spastic paraplegia due to a mutation in the KIF1A gene.</strong> Neuropediatrics 51: 146-153, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31805580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31805580</a>] [<a href="https://doi.org/10.1055/s-0039-3400988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31805580">Van Beusichem et al. (2020)</a> identified a de novo R216C mutation in a 15-year-old girl (patient 4) with NESCAVS. She did not have optic nerve atrophy or seizures, but showed cerebellar atrophy on brain imaging. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31805580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span class="mim-font">
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<strong>.0010 NESCAV SYNDROME</strong>
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KIF1A, ARG216HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs672601368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601368;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=rs672601368" 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=rs672601368" 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=RCV000191021 OR RCV000207040 OR RCV000997715 OR RCV003223396" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191021, RCV000207040, RCV000997715, RCV003223396" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191021...</a>
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<p>In a 16-year-old boy (patient 5) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#4" class="mim-tip-reference" title="Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H. <strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong> Ann. Clin. Transl. Neurol. 2: 623-635, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26125038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26125038</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26125038[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/acn3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26125038">Esmaeeli Nieh et al. (2015)</a> identified a de novo heterozygous c.647G-A transition (c.647G-A, NM_001244008) in the KIF1A gene, resulting in an arg216-to-his (R216H) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. Functional studies of this variant were not performed, but an in vitro microtubule gliding assay of a mutation at the same residue (R216C; <a href="#0009">601255.0009</a>) showed that the R216C mutant protein had no motility. This patient also carried a missense variant of unknown significance in the NID1 gene (T408K; <a href="/entry/131390">131390</a>), which may have explained his cataracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26125038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0011 NESCAV SYNDROME</strong>
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KIF1A, ARG254GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886041692 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886041692;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=rs886041692" 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=rs886041692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000326247 OR RCV000803981 OR RCV001078149 OR RCV001808727" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000326247, RCV000803981, RCV001078149, RCV001808727" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000326247...</a>
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<p>In an 8-year-old boy (patient 1) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#19" class="mim-tip-reference" title="Ohba, C., Haginoya, K., Osaka, H., Kubota, K., Ishiyama, A., Hiraide, T., Komaki, H., Sasaki, M., Miyatake, S., Nakashima, M., Tsurusaki, Y., Miyake, N., Tanaka, F., Saitsu, H., Matsumoto, N. <strong>De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.</strong> J. Hum. Genet. 60: 739-742, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26354034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26354034</a>] [<a href="https://doi.org/10.1038/jhg.2015.108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26354034">Ohba et al. (2015)</a> identified a de novo heterozygous c.761G-A transition (c.761G-A, NM_001244008.1) in the KIF1A gene, resulting in an arg254-to-gln (R254Q) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26354034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0012 NESCAV SYNDROME</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">rs879253888 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253888;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=rs879253888" 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=rs879253888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000236491 OR RCV000623278 OR RCV000763486 OR RCV000995795 OR RCV001857794 OR RCV004737388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000236491, RCV000623278, RCV000763486, RCV000995795, RCV001857794, RCV004737388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000236491...</a>
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<p>In a 27-year-old woman (patient 2) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#19" class="mim-tip-reference" title="Ohba, C., Haginoya, K., Osaka, H., Kubota, K., Ishiyama, A., Hiraide, T., Komaki, H., Sasaki, M., Miyatake, S., Nakashima, M., Tsurusaki, Y., Miyake, N., Tanaka, F., Saitsu, H., Matsumoto, N. <strong>De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.</strong> J. Hum. Genet. 60: 739-742, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26354034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26354034</a>] [<a href="https://doi.org/10.1038/jhg.2015.108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26354034">Ohba et al. (2015)</a> identified a de novo heterozygous c.760C-T transition (c.760C-T, NM_001224008.1) in the KIF1A gene, resulting in an arg254-to-trp (R254W) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26354034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 NESCAV SYNDROME</strong>
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KIF1A, GLY199ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553638614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553638614;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=rs1553638614" 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=rs1553638614" 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=RCV000520704 OR RCV001078151 OR RCV004584738" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000520704, RCV001078151, RCV004584738" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000520704...</a>
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<p>In a 6-year-old Brazilian boy (patient 2) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#7" class="mim-tip-reference" title="Hotchkiss, L., Donkervoort, S., Leach, M. E., Mohassel, P., Bharucha-Goebel, D. X., Bradley, N., Nguyen, D., Hu, Y., Gurgel-Giannetti, J., Bonnemann, C. G. <strong>Novel de novo mutations in KIF1A as a cause of hereditary spastic paraplegia with progressive central nervous system involvement.</strong> J. Child Neurol. 31: 1114-1119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27034427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27034427</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27034427[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/10.1177/0883073816639718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27034427">Hotchkiss et al. (2016)</a> identified a de novo heterozygous c.595G-A transition in the KIF1A gene, resulting in a gly199-to-arg (G199R) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to interfere with microtubule binding, possibly with a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27034427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786200949 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200949;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=rs786200949" 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=rs786200949" 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=RCV000167867 OR RCV000693147 OR RCV000762334 OR RCV001078152" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000167867, RCV000693147, RCV000762334, RCV001078152" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000167867...</a>
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<p>In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; <a href="/entry/610357">610357</a>), <a href="#30" class="mim-tip-reference" title="Ylikallio, E., Kim, D., Isohanni, P., Auranen, M., Kim, E., Lonnqvist, T., Tyynismaa, H. <strong>Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.</strong> Europ. J. Hum. Genet. 23: 1427-1430, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25585697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25585697</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25585697[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/ejhg.2014.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25585697">Ylikallio et al. (2015)</a> identified a heterozygous c.206C-T transition (c.206C-T, NM_001244008.1) in the KIF1A gene, resulting in a ser69-to-leu (S69L) substitution at a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25585697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30A, <a href="#2" class="mim-tip-reference" title="Citterio, A., Arnoldi, A., Panzeri, E., Merlini, L., D'Angelo, M. G., Musumeci, O., Toscano, A., Bondi, A., Martinuzzi, A., Bresolin, N., Bassi, M. T. <strong>Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.</strong> J. Neurol. 262: 2684-2690, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26410750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26410750</a>] [<a href="https://doi.org/10.1007/s00415-015-7899-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26410750">Citterio et al. (2015)</a> identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26410750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 members of a 3-generation family with SPG30A, <a href="#25" class="mim-tip-reference" title="Roda, R. H., Schindler, A. B., Blackstone, C. <strong>Multigeneration family with dominant SPG30 hereditary spastic paraplegia.</strong> Ann. Clin. Transl. Neurol. 4: 821-824, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29159194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29159194</a>] [<a href="https://doi.org/10.1002/acn3.452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29159194">Roda et al. (2017)</a> identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29159194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. <strong>KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.</strong> Europ. J. Hum. Genet. 28: 40-49, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31488895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31488895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31488895[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/s41431-019-0497-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31488895">Pennings et al. (2020)</a> identified a heterozygous S69L mutation in 3 members of a multigenerational family (P3) with SPG30A. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31488895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2050749062 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2050749062;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=rs2050749062" 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=rs2050749062" 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 father and daughter (family P16) with autosomal dominant spastic paraplegia-30A (SPG30A; <a href="/entry/610357">610357</a>), <a href="#23" class="mim-tip-reference" title="Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. <strong>KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.</strong> Europ. J. Hum. Genet. 28: 40-49, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31488895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31488895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31488895[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/s41431-019-0497-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31488895">Pennings et al. (2020)</a> identified a heterozygous c.1867C-T transition (c.1867C-T, NM_001244008.1) in the KIF1A gene, resulting in a gln623-to-ter (Q623X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31488895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs572662012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs572662012;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/rs572662012?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=rs572662012" 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=rs572662012" 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 father and his 2 daughters (family P20) with autosomal dominant spastic paraplegia-30A (SPG30A; <a href="/entry/610357">610357</a>), <a href="#23" class="mim-tip-reference" title="Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. <strong>KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.</strong> Europ. J. Hum. Genet. 28: 40-49, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31488895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31488895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31488895[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/s41431-019-0497-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31488895">Pennings et al. (2020)</a> identified a heterozygous c.3975C-G transversion in the KIF1A gene, resulting in a tyr1325-to-ter (Y1325X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31488895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001078155" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001078155" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001078155</a>
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<p>In a pair of monozygotic twin sisters (patients 5A and 5B) with NESCAV syndrome (NESCAVS; <a href="/entry/614255">614255</a>), <a href="#17" class="mim-tip-reference" title="Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. <strong>KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement.</strong> J. Peripher. Nerv. Syst. 25: 117-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32096284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32096284</a>] [<a href="https://doi.org/10.1111/jns.12368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32096284">Nemani et al. (2020)</a> identified a de novo heterozygous c.920G-C transversion (c.920G-C, NM_004321.6) in the KIF1A gene, resulting in an arg307-to-pro (R307P) substitution in the motor domain. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1016/j.ajhg.2011.02.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81562-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35078000" target="_blank">Full Text</a>]
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Klebe, S., Azzedine, H., Durr, A., Bastien, P., Bouslam, N., Elleuch, N., Forlani, S., Charon, C., Koenig, M., Melki, J., Brice, A., Stevanin, G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16434418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16434418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16434418" 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/awl012" target="_blank">Full Text</a>]
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<a id="Klebe2012" class="mim-anchor"></a>
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Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others.
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<strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22258533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2011.261" target="_blank">Full Text</a>]
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<a id="Klopfenstein2002" class="mim-anchor"></a>
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Klopfenstein, D. R., Tomishige, M., Stuurman, N., Vale, R. D.
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<strong>Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015984</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12015984[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=12015984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(02)00708-0" target="_blank">Full Text</a>]
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<a id="Langlois2016" class="mim-anchor"></a>
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Langlois, S., Tarailo-Graovac, M., Sayson, B., Drogemoller, B., Swenerton, A., Ross, C. J. D., Wasserman, W. W., van Karnebeek, C. D. M.
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<strong>De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.</strong>
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[<a href="https://doi.org/10.1111/jns.12368" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1096621" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.06.013" target="_blank">Full Text</a>]
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Europ. J. Hum. Genet. 23: 1427-1430, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25585697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25585697</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25585697[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=25585697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2014.297" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Yonekawa1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yonekawa, Y., Harada, A., Okada, Y., Funakoshi, T., Kanai, Y., Takei, Y., Terada, S., Noda, T., Hirokawa, N.
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<strong>Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.</strong>
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|
J. Cell Biol. 141: 431-441, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9548721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9548721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9548721[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=9548721" 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/10.1083/jcb.141.2.431" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 01/11/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/06/2020<br>Cassandra L. Kniffin - updated : 04/15/2020<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Cassandra L. Kniffin - updated : 8/8/2012<br>Matthew B. Gross - updated : 6/21/2012<br>Ada Hamosh - updated : 9/23/2011<br>Cassandra L. Kniffin - updated : 9/15/2011<br>Ada Hamosh - updated : 8/30/2004<br>Ada Hamosh - updated : 7/31/2003<br>Ada Hamosh - updated : 11/13/2002<br>Stylianos E. Antonarakis - updated : 5/13/2002<br>Ada Hamosh - updated : 5/22/2001<br>Stylianos E. Antonarakis - updated : 2/8/2000<br>Victor A. McKusick - updated : 4/26/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Moyra Smith : 5/10/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 11/26/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/09/2024<br>carol : 07/05/2024<br>mgross : 01/11/2021<br>carol : 08/29/2020<br>mgross : 08/06/2020<br>carol : 04/16/2020<br>ckniffin : 04/15/2020<br>carol : 04/10/2020<br>carol : 04/09/2020<br>carol : 12/16/2019<br>carol : 08/29/2017<br>joanna : 06/24/2016<br>alopez : 2/24/2016<br>alopez : 9/21/2015<br>ckniffin : 9/21/2015<br>mcolton : 2/10/2015<br>carol : 9/16/2013<br>terry : 11/15/2012<br>carol : 8/22/2012<br>ckniffin : 8/8/2012<br>terry : 7/6/2012<br>mgross : 6/21/2012<br>alopez : 10/3/2011<br>terry : 9/23/2011<br>carol : 9/16/2011<br>carol : 9/16/2011<br>ckniffin : 9/15/2011<br>alopez : 9/2/2004<br>terry : 8/30/2004<br>alopez : 8/4/2003<br>terry : 7/31/2003<br>alopez : 11/14/2002<br>terry : 11/13/2002<br>mgross : 5/13/2002<br>mgross : 5/13/2002<br>alopez : 5/23/2001<br>terry : 5/22/2001<br>alopez : 8/15/2000<br>mgross : 2/8/2000<br>alopez : 5/18/1999<br>mgross : 5/7/1999<br>mgross : 4/29/1999<br>mgross : 4/29/1999<br>terry : 4/26/1999<br>mark : 9/16/1997<br>carol : 5/13/1996<br>carol : 5/12/1996
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601255
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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KINESIN FAMILY MEMBER 1A; KIF1A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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AXONAL TRANSPORTER OF SYNAPTIC VESICLES; ATSV<br />
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UNC104, C. ELEGANS, HOMOLOG OF; UNC104<br />
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KINESIN, HEAVY CHAIN, MEMBER 1A, MOUSE, HOMOLOG OF
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KIF1A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763377006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 2q37.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:240,713,767-240,821,403 </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>
|
|
<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="4">
|
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<span class="mim-font">
|
|
2q37.3
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
NESCAV syndrome
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
614255
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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>
|
|
<span class="mim-font">
|
|
Neuropathy, hereditary sensory, type IIC
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
614213
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
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 30, autosomal dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
610357
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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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 30, 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">
|
|
620607
|
|
</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<span class="mim-text-font">
|
|
<p>The KIF1A gene encodes a motor protein involved in the anterograde transport of synaptic-vesicle (SV) precursors along axons (summary by Riviere et al., 2011). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>In a search for candidate genes for the tuberous sclerosis-1 (TSC1; 191100) disease locus, Furlong et al. (1996) identified a novel gene, the axonal transporter of synaptic vesicles (ATSV) gene, that maps adjacent to a CpG island, approximately 80 kb centromeric of the ABO (110300) locus on chromosome 9q34.1-q34.2. (The ATSV gene was later mapped to chromosome 2q37; see 'Mapping,' below.) Furlong et al. (1996) obtained 7 kb of continuous sequence from a series of overlapping cosmid clones and corresponding cDNA clones which were isolated from a brain cDNA library. Sequence analysis revealed an open reading frame of 5,070 bp encoding a putative protein which shows 97% identity at the amino acid level to the mouse KIF1A gene product and 42% identity with the C. elegans unc-104 genes. Both KIF1A and unc-104 function in the anterograde axonal transport of synaptic vesicles and are members of the kinesin gene family (see 600025). The ATSV gene is transcribed in the direction 9qter to 9cen. A CpG island was found at the 3-prime end of the gene. The ATSV gene probes detected a NotI polymorphism which occurred with a frequency of 2%. Furlong et al. (1996) found no supporting evidence for ATSV as the candidate TSC1 gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Nomenclature</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<span class="mim-text-font">
|
|
<p>Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF1A belongs to the kinesin-3 family. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</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>Kinesin-related proteins constitute a large superfamily of microtubule-dependent proteins that mediate specific and diverse motile processes, including intracellular transport and cell division. The human ATSV protein is a member of the kinesin family and shows 95% identity to the KIF1A protein of mouse (Okada et al., 1995). KIF1A is an anterograde motor protein that transports membranous organelles along axonal microtubules. Its cargo includes a subset of precursors for synaptic vesicles: synaptophysin (313475), synaptotagmin (185605), and Rab3A (179490). The phenotype of KIF1A knockout mice includes motor and sensory disturbances, a reduction in the density of synaptic vesicles in nerve terminals, and accumulation of clear vesicles in nerve cell bodies (Yonekawa et al., 1998). It can be hypothesized that ATSV (and KIF1A in the mouse) may play a critical role in the development of axonal neuropathies resulting from impaired axonal transport. </p><p>Using an in vitro motility assay, Klopfenstein et al. (2002) showed that Dictyostelium Unc104 uses a lipid-binding pleckstrin homology (PH) domain to dock onto membrane cargo. Through its PH domain, Unc104 could transport phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2)-containing liposomes with similar properties to native vesicles. Liposome movement by monomeric Unc104 motors showed a steep dependence on PtdIns(4,5)P2 concentration, even though liposome binding was noncooperative. This switch-like transition for movement could be shifted to lower PtdIns(4,5)P2 concentrations by the addition of cholesterol/sphingomyelin or GM1 ganglioside/cholera toxin, conditions that produced raft-like behavior of Unc104 bound to lipid bilayers. The authors concluded that clustering of Unc104 in PtdIns(4,5)P2-containing rafts provides a trigger for membrane transport. </p><p>Tomishige et al. (2002) demonstrated that KIF1A can dimerize and move unidirectionally and processively with rapid velocities characteristic of transport in living cells. Their results suggested that KIF1A operates in vivo by a mechanism similar to conventional kinesin and that regulation of motor dimerization may be used to control transport by this class of kinesins. </p><p>In a yeast 2-hybrid screen using a human fetal brain cDNA library, Riviere et al. (2011) found that the KIF1A gene interacted with the HSN2 exon of WNK1 (605232). Immunoprecipitation studies showed that the 2 proteins localized in cultured primary sensory neurons prepared from adult mouse dorsal root ganglia. Both proteins were found to localize in cell bodies and along axons, suggesting a role in axonal transport. </p><p>Using a mass spectrometry approach, Stucchi et al. (2018) identified TANC2 (615047), liprin-alpha-2 (PPFIA2; 603143), and the calcium-binding protein calmodulin (see CALM1, 114180) as direct binding partners of KIF1A, the primary motor protein for SVs and dense core vesicles (DCVs). Analysis with rat hippocampal neurons revealed that calcium enhanced Kif1a binding to DCVs and increased vesicle motility by acting through calmodulin. Tanc2 and liprin-alpha-2 were enriched in dendritic spines but were not part of the Kif1a cargo complex. Instead, they acted as postsynaptic density scaffolds to stop and capture Kif1a-bound DCVs upon dendritic spine entry. Knockdown experiments showed that depletion of Tanc2, Kif1a, or liprin-alpha-2 affected rat dendritic spine density and morphology. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</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>X-Ray Crystallography and Cryoelectron Microscopy</em></strong></p><p>
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Kikkawa et al. (2000) generated a 15-angstrom resolution map of the KIF1A-microtubule complex, which allowed clear visualization of the K loop, a 12-amino acid insert in the L12 region, as an arm-like structure. Furthermore, this high-resolution model revealed how kinesin motors interact with microtubules. KIF1A has 3 microtubule-binding sites, termed MB1, MB2, and MB3. MB3 is the unique arm-like projection containing the K loop. </p><p>Kikkawa et al. (2001) studied the monomeric kinesin motor KIF1A using x-ray crystallography and cryoelectron microscopy, to allow analysis of force-generating conformational changes at atomic resolution. Their analysis revealed the motor in its 2 functionally critical states, complexed with ADP and with a nonhydrolyzable analog of ATP. The conformational change observed between the 2 structures of the KIF1A catalytic core is modular, extends to all kinesins, and is similar to the conformational change used by myosin motors and G proteins. Docking of the ADP-bound and ATP-like crystallographic models of KIF1A into the corresponding cryoelectron microscopy maps suggests a rationale for the plus-end directional bias associated with the kinesin catalytic core. </p><p>Nitta et al. (2004) reported crystal structures of monomeric kinesin KIF1A with 3 transition-state analogs: adenylyl imidodiphosphate (AMP-PNP), adenosine diphosphate (ADP)-vanadate, and ADP-AlFx (aluminofluoride complexes). These structures, together with known structures of the ADP-bound state and the adenylyl-(beta,gamma-methylene) diphosphate (AMP-PCP)-bound state, show that kinesin uses 2 microtubule-binding loops in an alternating manner to change its interaction with microtubules during the ATP hydrolysis cycle; loop L11 is extended into the AMP-PNP structure, whereas loop L12 is extended in the ADP structure. ADP-vanadate displays an intermediate structure in which a conformational change in 2 switch regions causes both loops to be raised from the microtubule, thus actively detaching kinesin. </p><p><strong><em>Optical Trapping</em></strong></p><p>
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By measuring its movement with an optical trapping system, Okada et al. (2003) used KIF1A as a model molecule to demonstrate that a single ATP hydrolysis triggers a single stepping movement of a single KIF1A monomer. The step size is distributed stochastically around multiples of 8 nm with a gaussian-like envelope and a standard deviation of 15 nm. On average, the step is directional to the microtubule's plus-end against a load force of up to 0.15 pN. As the source for this directional movement, Okada et al. (2003) showed that KIF1A moves to the microtubule's plus-end by approximately 3 nm on average on binding to the microtubule, presumably by preferential binding to tubulin on the plus-end side. </p>
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</span>
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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>Amyotrophic lateral sclerosis-4 (ALS4; 602433) is an autosomal dominant, juvenile-onset motor systems disease with an axonal phenotype that includes prominent axonal swelling. The ALS4 locus maps to 9q34, a region that overlaps the putative ATSV gene region, making it an attractive positional and functional candidate gene for ALS4. Keller et al. (1999) investigated the ATSV gene as a candidate gene for ALS4 and failed to confirm the assignment of the ATSV gene to chromosome 9. By PCR analysis of a human/rodent somatic cell hybrid panel and by FISH, they instead mapped the human ATSV gene to 2q37. The ATSV gene therefore becomes a candidate gene for other peripheral nerve disorders involving altered axonal transport mapping to 2q37. Keller et al. (1999) suggested that a limited stretch of sequence identity to the ATSV transcript in the previously identified region of 9q34 may have led to the prior conclusion that the ATSV gene maps to chromosome 9. Alternatively, a chimerism in the YAC clone used to generate the cosmid in that previous study may have led to the erroneous mapping of the ATSV gene to 9q34. </p>
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</span>
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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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<span class="mim-text-font">
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<p><strong><em>Spastic Paraplegia 30A, Autosomal Dominant</em></strong></p><p>
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In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Ylikallio et al. (2015) identified a heterozygous mutation (S69L; 601255.0014) in the KIF1A gene; the substitution affected a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30A, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 3 members of a 3-generational family with SPG30, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 4 patients (patients 6, 8A, 8B, and 9), including 2 sibs, with SPG30A, Nemani et al. (2020) identified heterozygous mutations in the KIF1A gene. Three patients carried the S69L mutation, whereas 1 had an R11Q mutation. Functional studies of the variants were not performed. </p><p>In 23 probands with SPG30A, Pennings et al. (2020) identified 19 different heterozygous point mutations in the KIF1A gene. There were 11 missense variants in the motor domain (see, e.g., S69L, 601255.0014), as well as 9 variants outside of the motor domain. Six of these 9 mutations were nonsense or frameshift mutations (see, e.g., 601255.0015 and 601255.0016) predicted to result in a loss of function. Three variants were considered to be 'variants of unknown significance'. Functional studies of the variants and studies of patient cells were not performed. The findings suggested that autosomal dominant SPG30 can be caused by either missense or loss-of-function mutations. The patients were ascertained from a cohort of 347 probands with SPG who underwent exome sequencing. </p><p><strong><em>Spastic Paraplegia 30B, Autosomal Recessive</em></strong></p><p>
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By homozygosity mapping, exome sequencing, and examination of candidate genes, Erlich et al. (2011) identified a homozygous mutation in the KIF1A gene (A255V; 601255.0001) in 3 Palestinian sibs with autosomal recessive spastic paraplegia-30B (SPG30B; 620607). </p><p>Klebe et al. (2012) identified a homozygous mutation in the KIF1A gene (R350G; 601255.0005) in affected members of a consanguineous Algerian family with SPG30B originally reported by Klebe et al. (2006). Another Palestinian family with the disorder was found to be homozygous for the A255V mutation. </p><p><strong><em>Functional Studies of SPG30-Associated KIF1A Mutations</em></strong></p><p>
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Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including A255V and R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutations in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. The authors concluded that hyperactivation of kinesin motor activity can cause motor neuron disease in humans. </p><p><strong><em>Hereditary Sensory Neuropathy, Type IIC</em></strong></p><p>
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By genomewide homozygosity mapping followed by candidate gene analysis in a consanguineous Afghan family with hereditary sensory neuropathy type IIC (HSN2C; 614213), Riviere et al. (2011) identified a homozygous truncating mutation in the KIF1A gene (601255.0002). Screening of this gene in 112 unrelated patients with HSN identified 2 additional families with the same mutation and 1 patient who was compound heterozygous for 2 mutations (601255.0002 and 601255.0003). </p><p><strong><em>NESCAV Syndrome</em></strong></p><p>
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In a patient with NESCAV syndrome (NESCAVS; 614255), Hamdan et al. (2011) identified a missense mutation (T99M; 601255.0004) in the KIF1A gene. The mutation affected localization of the KIF1A protein in neurites. </p><p>In 14 patients, including a pair of monozygotic twins, with NESCAVS, Lee et al. (2015) identified 11 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0006-601255.0008). The mutations in 12 families were found by exome sequencing; the mutation in 1 family was found by targeted next-generation sequencing. All the mutations occurred at conserved residues in the motor domain. In vitro functional expression studies of 5 of the mutations in rat hippocampal cells showed that they resulted in greatly reduced distal localization in neurites compared to wildtype. The patients had intellectual disability with variable cerebellar atrophy, spastic paraparesis, optic atrophy, peripheral neuropathy, and seizures. Lee et al. (2015) hypothesized that, since KIF1A functions as an active dimer, heterozygous missense mutations may exert a dominant-negative effect, which may explain the severe phenotype compared to those with recessive mutations. </p><p>In 6 unrelated patients with NESCAVS, Esmaeeli Nieh et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0007, 601255.0009-601255.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred at conserved residues in the motor domain, and in vitro functional microtubule gliding assays of several of the mutations showed that they resulted in a loss of motility with evidence for a dominant-negative effect. The patients had a severe neurodegenerative encephalopathy, with progressive cerebral and cerebellar atrophy, thus expanding the phenotype associated with de novo KIF1A mutations. </p><p>In 5 unrelated patients with NESCAVS, Ohba et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0011 and 601255.0012). All of the mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, affected highly conserved residues in the motor domain. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that the variants would destabilize the protein or affect protein function. </p><p>In 2 unrelated patients with NESCAVS, Hotchkiss et al. (2016) identified 2 de novo heterozygous missense mutations in the KIF1A gene (see, e.g., G199R, 601255.0013). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variants and studies of patient cells were not performed, but both occurred in the motor domain and were predicted to interfere with microtubule binding, possibly with a dominant-negative effect. </p><p>In 2 unrelated patients with NESCAVS, Van Beusichem et al. (2020) identified de novo heterozygous missense variants in the KIF1A gene (R380W; R216C, 601255.0009). Functional studies of the variants and studies of patient cells were not performed. In a review of previously reported cases, the authors concluded that there is no apparent genotype/phenotype correlation. </p><p>In a 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, Samanta and Gokden (2019) identified a de novo heterozygous E253K mutation in the KIF1A gene (601255.0007). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. </p><p>In 8 patients with NESCAVS, Nemani et al. (2020) identified de novo heterozygous mutations in the KIF1A gene (see, e.g., R254W, 601255.0012 and R307P, 601255.0017). All except 1 were missense variants affecting the kinesin motor domain; 1 was a splice site mutation. Two patients with profound encephalopathy carried the heterozygous E253K mutation. Functional studies of the variants were not performed. </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>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Klebe et al. (2012) observed that patients with truncating mutations in the KIF1A gene (see, e.g., 601255.0002) tended to present with a peripheral nervous system disorder (HSN2C), whereas those with missense mutations (see, e.g., 601255.0001) tended to present with an upper motor neuron syndrome of the central nervous system (SPG30). However, some patients with central nervous system spasticity also developed dysfunction of the peripheral nervous system, and only a few families with KIF1A mutations had been reported by that time. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Yonekawa et al. (1998) found that Kif1a-null mice died within several days after birth and showed severe motor and sensory disturbances, including ataxia, abnormal limb movements, and diminished pain response. Analysis of spinal cord cells and axons showed decreased densities of nerve terminals and synaptic vesicles in the nerve terminals and abnormal clustering of small vesicles in nerve cell bodies, suggesting a defect in anterograde axonal transport. Mutant mice also showed significant neuronal and axonal degeneration and death, and neuronal degeneration and death also occurred in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wildtype neurons or exposure to a low concentration of glutamate, suggesting that the neuronal death was due to lack of afferent stimulation resulting from lack of synaptic transmission. The findings indicated that Kif1a transports synaptic vesicle precursors and that this action plays a critical role in viability, maintenance, and function of neurons. </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>17 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 SPASTIC PARAPLEGIA 30B, AUTOSOMAL RECESSIVE</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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KIF1A, ALA255VAL
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<br />
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SNP: rs387906798,
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ClinVar: RCV004584596
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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 3 Palestinian sibs with autosomal recessive spastic paraplegia-30B (SPG30B; 620607), Erlich et al. (2011) identified a homozygous mutation in the KIF1A gene, resulting in an ala255-to-val (A255V) substitution in a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was found in 3 of 573 individuals from the same ethnic origin, yielding a carrier frequency of 1:191 in this population. The patients had early childhood onset of pure spasticity and hyperreflexia affecting the lower limbs; sensation was intact. </p><p>Klebe et al. (2012) identified a homozygous A255V mutation in affected members of a consanguineous Palestinian family with SPG30B. Age at onset ranged from 10 to 39 years, and patients had spastic gait with axonal sensorineuropathy after long disease duration. None had cerebellar signs. </p><p>In rat hippocampal neurons, Lee et al. (2015) found that the A255V mutation resulted in mildly decreased distal localization in neurites (80.8% compared to wildtype). </p><p>In an in vitro microtubule gliding assay, Esmaeeli Nieh et al. (2015) showed that the mutant A255V protein had motility similar to wildtype. </p><p>Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including A255V, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. </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 NEUROPATHY, HEREDITARY SENSORY, TYPE IIC</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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KIF1A, 1-BP DEL, 2840T
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<br />
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SNP: rs587778791,
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gnomAD: rs587778791,
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ClinVar: RCV000023085, RCV000056104, RCV000639798, RCV004537254
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 3 unrelated families with hereditary sensory neuropathy IIC (HSN2C; 614213), Riviere et al. (2011) identified a homozygous 1-bp deletion (2840delT) in the alternatively spliced exon 25b of the KIF1A gene, predicted to cause a frameshift (Leu947Argfs*4). The mutation was not found in 665 European controls. One of the families was Afghan, 1 was Turkish, and 1 was Belgian; 2 of the families were consanguineous. Another Belgian patient, with a more severe disorder, was compound heterozygous for 2840delT and a 1-bp insertion (5271dupC; 601255.0003) in exon 46, predicted to cause a frameshift and premature termination (Ser1758GlnfsTer7). </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 NEUROPATHY, HEREDITARY SENSORY, TYPE IIC</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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KIF1A, 1-BP DUP, 5271C
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<br />
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SNP: rs587778798,
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ClinVar: RCV000023086, RCV000056120
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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 1-bp duplication in exon 46 of the KIF1A gene (5271dupC) that was found in compound heterozygous state in a patient with hereditary sensory neuropathy IIC (HSN2C; 614213) by Riviere et al., 2011, see 601255.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 NESCAV SYNDROME</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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KIF1A, THR99MET ({dbSNP rs387906799})
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<br />
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SNP: rs387906799,
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gnomAD: rs387906799,
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ClinVar: RCV000023087, RCV000207102, RCV000235916, RCV000690609, RCV004541014
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3.5-year-old girl (patient 7) with NESCAV syndrome (NESCAVS; 614255), Hamdan et al. (2011) identified a heterozygous C-to-T transition at nucleotide 296 of the KIF1A gene, resulting in a thr-to-met substitution at codon 99 (T99M). The patient also had axial hypotonia with peripheral spasticity, and mild atrophy of the vermian region of the cerebellum on MRI. This mutation was not identified in the patient's parents or in 285 control chromosomes. Functional assays showed that the mutation affected the localization of KIF1A from distal regions of neurites, as seen in wildtype, to reduced distal localization and increased accumulation throughout the cell body and proximal neurites in cells transfected with a mutant protein. </p><p>Lee et al. (2015) identified a de novo heterozygous T99M mutation (c.296C-T, NM_001244008.1) in 2 unrelated girls (patients 1 and 2) with NESCAVS. The mutation occurred at a conserved residue in the nucleotide-binding pocket in the motor domain and was predicted to abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (15.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. </p><p>Esmaeeli Nieh et al. (2015) identified a de novo heterozygous T99M mutation in 2 unrelated patients (patients 1 and 2) with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility. </p><p>Okamoto et al. (2014) and Langlois et al. (2016) identified de novo heterozygous T99M mutations in 2 unrelated patients with NESCAVS. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the findings further suggested that a severe phenotype is associated with this mutation. Okamoto et al. (2014) speculated that since the KIF1A protein homodimerizes, the T99M mutation may cause a dominant-negative effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SPASTIC PARAPLEGIA 30B, AUTOSOMAL RECESSIVE</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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KIF1A, ARG350GLY
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<br />
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SNP: rs387907259,
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ClinVar: RCV000030681, RCV004584597
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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 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spastic paraplegia-30B (SPG30B; 620607), who were originally reported by Klebe et al. (2006), Klebe et al. (2012) identified a homozygous 1048C-G transversion in exon 13 of the KIF1A gene, resulting in an arg350-to-gly (R350G) substitution at a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was not found in 970 control chromosomes. The mutation occurred at the end of the motor domain in close vicinity to the neck linker that has an important role in directionality. Affected individuals had spasticity, sensorimotor axonal neuropathy, and mild cerebellar signs. </p><p>In rat hippocampal neurons, Lee et al. (2015) found that the R350G mutation resulted in greatly reduced distal localization in neurites (20.7% compared to wildtype). </p><p>Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding human mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NESCAV SYNDROME</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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KIF1A, SER215ARG
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<br />
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SNP: rs672601367,
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ClinVar: RCV000149479, RCV001090762, RCV003998180
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old boy (patient 6) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.643A-C transversion (c.643A-C, NM_001244008.1) in the KIF1A gene, resulting in a ser215-to-arg (S215R) substitution at a conserved residue in the nucleotide-binding pocket in the motor domain. Structural modeling predicted that the mutation would abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (13.5% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 NESCAV SYNDROME</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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KIF1A, GLU253LYS
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<br />
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SNP: rs672601369,
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ClinVar: RCV000149481, RCV000488961, RCV000850486, RCV001813759
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated girls (patients 8 and 9) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.757G-A transition (c.757G-A, NM_001244008.1) in the KIF1A gene, resulting in a glu253-to-lys (E253K) substitution at a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would disrupt this structure, suppress ATP gamma-phosphate release, and prevent additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (19.3% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. Both girls had a severe phenotype with optic atrophy and cerebral and cerebellar atrophy, resulting in death before age 4 years. </p><p>Esmaeeli Nieh et al. (2015) identified a de novo heterozygous E253K mutation in a patient with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility and acted in a dominant-negative manner. </p><p>In a 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, Samanta and Gokden (2019) identified a de novo heterozygous E253K mutation in the KIF1A gene. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. </p><p>Nemani et al. (2020) identified de novo heterozygous E253K mutations in 2 unrelated infants (patients 1 and 2) with a severe form of NESCAV syndrome. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 NESCAV SYNDROME</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KIF1A, ALA202PRO
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<br />
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SNP: rs672601366,
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ClinVar: RCV000149478
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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 30-month-old girl (patient 5) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.604G-C transversion (c.604G-C, NM_001244008.1) in the KIF1A gene, resulting in an ala202-to-pro (A202P) substitution near a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would induce a conformational change, likely disrupting efficient ATP gamma-phosphate release and additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (9.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 NESCAV SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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KIF1A, ARG216CYS
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<br />
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SNP: rs797045164,
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ClinVar: RCV000191020, RCV000207243, RCV001255726, RCV001269905, RCV001389787, RCV001796966, RCV002514079
|
|
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old girl (patient 3) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.646C-T transition (c.646C-T, NM_001244008) in the KIF1A gene, resulting in an arg216-to-cys (R216C) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. An in vitro microtubule gliding assay showed that the mutant protein had no motility. </p><p>Van Beusichem et al. (2020) identified a de novo R216C mutation in a 15-year-old girl (patient 4) with NESCAVS. She did not have optic nerve atrophy or seizures, but showed cerebellar atrophy on brain imaging. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NESCAV SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KIF1A, ARG216HIS
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs672601368,
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|
|
|
|
|
|
|
ClinVar: RCV000191021, RCV000207040, RCV000997715, RCV003223396
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old boy (patient 5) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.647G-A transition (c.647G-A, NM_001244008) in the KIF1A gene, resulting in an arg216-to-his (R216H) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. Functional studies of this variant were not performed, but an in vitro microtubule gliding assay of a mutation at the same residue (R216C; 601255.0009) showed that the R216C mutant protein had no motility. This patient also carried a missense variant of unknown significance in the NID1 gene (T408K; 131390), which may have explained his cataracts. </p>
|
|
</span>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NESCAV SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KIF1A, ARG254GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886041692,
|
|
|
|
|
|
|
|
ClinVar: RCV000326247, RCV000803981, RCV001078149, RCV001808727
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old boy (patient 1) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.761G-A transition (c.761G-A, NM_001244008.1) in the KIF1A gene, resulting in an arg254-to-gln (R254Q) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NESCAV SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KIF1A, ARG254TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879253888,
|
|
|
|
|
|
|
|
ClinVar: RCV000236491, RCV000623278, RCV000763486, RCV000995795, RCV001857794, RCV004737388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 27-year-old woman (patient 2) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.760C-T transition (c.760C-T, NM_001224008.1) in the KIF1A gene, resulting in an arg254-to-trp (R254W) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 NESCAV SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KIF1A, GLY199ARG
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|
|
<br />
|
|
|
|
SNP: rs1553638614,
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|
|
|
|
|
|
|
ClinVar: RCV000520704, RCV001078151, RCV004584738
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old Brazilian boy (patient 2) with NESCAV syndrome (NESCAVS; 614255), Hotchkiss et al. (2016) identified a de novo heterozygous c.595G-A transition in the KIF1A gene, resulting in a gly199-to-arg (G199R) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to interfere with microtubule binding, possibly with a dominant-negative effect. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SPASTIC PARAPLEGIA 30A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
KIF1A, SER69LEU
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<br />
|
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|
|
SNP: rs786200949,
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|
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ClinVar: RCV000167867, RCV000693147, RCV000762334, RCV001078152
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Ylikallio et al. (2015) identified a heterozygous c.206C-T transition (c.206C-T, NM_001244008.1) in the KIF1A gene, resulting in a ser69-to-leu (S69L) substitution at a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30A, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 3 members of a 3-generation family with SPG30A, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. </p><p>Pennings et al. (2020) identified a heterozygous S69L mutation in 3 members of a multigenerational family (P3) with SPG30A. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 SPASTIC PARAPLEGIA 30A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KIF1A, GLN623TER
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<br />
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SNP: rs2050749062,
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ClinVar: RCV001078153
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and daughter (family P16) with autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Pennings et al. (2020) identified a heterozygous c.1867C-T transition (c.1867C-T, NM_001244008.1) in the KIF1A gene, resulting in a gln623-to-ter (Q623X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed. </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>.0016 SPASTIC PARAPLEGIA 30A, AUTOSOMAL DOMINANT</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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KIF1A, TYR1325TER
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<br />
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SNP: rs572662012,
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gnomAD: rs572662012,
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ClinVar: RCV001078154
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and his 2 daughters (family P20) with autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Pennings et al. (2020) identified a heterozygous c.3975C-G transversion in the KIF1A gene, resulting in a tyr1325-to-ter (Y1325X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed. </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>.0017 NESCAV SYNDROME</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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KIF1A, ARG307PRO
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<br />
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SNP: rs1064793161,
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ClinVar: RCV001078155
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a pair of monozygotic twin sisters (patients 5A and 5B) with NESCAV syndrome (NESCAVS; 614255), Nemani et al. (2020) identified a de novo heterozygous c.920G-C transversion (c.920G-C, NM_004321.6) in the KIF1A gene, resulting in an arg307-to-pro (R307P) substitution in the motor domain. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Chiba, K., Takahashi, H., Chen, M., Obinata, H., Arai, S., Hashimoto, K., Oda, T., McKenney, R. J., Niwa, S.
|
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<strong>Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.</strong>
|
|
Proc. Nat. Acad. Sci. 116: 18429-18434, 2019.
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[PubMed: 31455732]
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[Full Text: https://doi.org/10.1073/pnas.1905690116]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Citterio, A., Arnoldi, A., Panzeri, E., Merlini, L., D'Angelo, M. G., Musumeci, O., Toscano, A., Bondi, A., Martinuzzi, A., Bresolin, N., Bassi, M. T.
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<strong>Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.</strong>
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J. Neurol. 262: 2684-2690, 2015.
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[PubMed: 26410750]
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[Full Text: https://doi.org/10.1007/s00415-015-7899-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Erlich, Y., Edvardson, S., Hodges, E., Zenvirt, S., Thekkat, P., Shaag, A., Dor, T., Hannon, G. J., Elpeleg, O.
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<strong>Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.</strong>
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Genome Res. 21: 658-664, 2011.
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[PubMed: 21487076]
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[Full Text: https://doi.org/10.1101/gr.117143.110]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Esmaeeli Nieh, S., Madou, M. R. Z., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., Vale, R. D., Barkovich, A. J., Sherr, E. H.
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|
<strong>De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.</strong>
|
|
Ann. Clin. Transl. Neurol. 2: 623-635, 2015.
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[PubMed: 26125038]
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[Full Text: https://doi.org/10.1002/acn3.198]
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</p>
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<li>
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<p class="mim-text-font">
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Furlong, R. A., Zhou, C. Y., Ferguson-Smith, M. A., Affara, N. A.
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<strong>Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9q34.</strong>
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Genomics 33: 421-429, 1996.
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[PubMed: 8661001]
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[Full Text: https://doi.org/10.1006/geno.1996.0217]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others.
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<strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong>
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Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
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[PubMed: 21376300]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.02.001]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hotchkiss, L., Donkervoort, S., Leach, M. E., Mohassel, P., Bharucha-Goebel, D. X., Bradley, N., Nguyen, D., Hu, Y., Gurgel-Giannetti, J., Bonnemann, C. G.
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<strong>Novel de novo mutations in KIF1A as a cause of hereditary spastic paraplegia with progressive central nervous system involvement.</strong>
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J. Child Neurol. 31: 1114-1119, 2016.
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[PubMed: 27034427]
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[Full Text: https://doi.org/10.1177/0883073816639718]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Keller, M. P., Seifried, B. A., Rabin, B. A., Chance, P. F.
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<strong>Mapping of the kinesin-related gene ATSV to chromosome 2q37.</strong>
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|
Hum. Genet. 104: 254-256, 1999.
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[PubMed: 10323250]
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[Full Text: https://doi.org/10.1007/s004390050944]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kikkawa, M., Okada, Y., Hirokawa, N.
|
|
<strong>15-angstrom resolution model of the monomeric kinesin motor, KIF1A.</strong>
|
|
Cell 100: 241-252, 2000.
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|
|
[PubMed: 10660047]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81562-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kikkawa, M., Sablin, E. P., Okada, Y., Yajima, H., Fletterick, R. J., Hirokawa, N.
|
|
<strong>Switch-based mechanism of kinesin motors.</strong>
|
|
Nature 411: 439-445, 2001.
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[PubMed: 11373668]
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[Full Text: https://doi.org/10.1038/35078000]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Klebe, S., Azzedine, H., Durr, A., Bastien, P., Bouslam, N., Elleuch, N., Forlani, S., Charon, C., Koenig, M., Melki, J., Brice, A., Stevanin, G.
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<strong>Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.</strong>
|
|
Brain 129: 1456-1462, 2006.
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[PubMed: 16434418]
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[Full Text: https://doi.org/10.1093/brain/awl012]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Klebe, S., Lossos, A., Azzedine, H., Mundwiller, E., Sheffer, R., Gaussen, M., Marelli, C., Nawara, M., Carpentier, W., Meyer, V., Rastetter, A., Martin, E., and 11 others.
|
|
<strong>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.</strong>
|
|
Europ. J. Hum. Genet. 20: 645-649, 2012.
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|
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|
[PubMed: 22258533]
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[Full Text: https://doi.org/10.1038/ejhg.2011.261]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Klopfenstein, D. R., Tomishige, M., Stuurman, N., Vale, R. D.
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<strong>Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor.</strong>
|
|
Cell 109: 347-358, 2002.
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[PubMed: 12015984]
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[Full Text: https://doi.org/10.1016/s0092-8674(02)00708-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Langlois, S., Tarailo-Graovac, M., Sayson, B., Drogemoller, B., Swenerton, A., Ross, C. J. D., Wasserman, W. W., van Karnebeek, C. D. M.
|
|
<strong>De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.</strong>
|
|
Europ. J. Hum. Genet. 24: 949-953, 2016.
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[PubMed: 26486474]
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[Full Text: https://doi.org/10.1038/ejhg.2015.217]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lawrence, C. J., Dawe, R. K., Christie, K. R., Cleveland, D. W., Dawson, S. C., Endow, S. A., Goldstein, L. S. B., Goodson, H. V., Hirokawa, N., Howard, J., Malmberg, R. L., McIntosh, J. R., and 10 others.
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<strong>A standardized kinesin nomenclature.</strong>
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J. Cell Biol. 167: 19-22, 2004.
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[PubMed: 15479732]
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[Full Text: https://doi.org/10.1083/jcb.200408113]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lee, J.-R., Srour, M., Kim, D., Hamdan, F. F., Lim, S.-H., Brunel-Guitton, C., Decarie, J.-C., Rossingnol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., and 18 others.
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|
<strong>De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.</strong>
|
|
Hum. Mutat. 36: 69-78, 2015.
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|
|
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|
[PubMed: 25265257]
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[Full Text: https://doi.org/10.1002/humu.22709]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P.
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<strong>KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement.</strong>
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|
J. Peripher. Nerv. Syst. 25: 117-124, 2020.
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[PubMed: 32096284]
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[Full Text: https://doi.org/10.1111/jns.12368]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nitta, R., Kikkawa, M., Okada, Y., Hirokawa, N.
|
|
<strong>KIF1A alternately uses two loops to bind microtubules.</strong>
|
|
Science 305: 678-683, 2004.
|
|
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|
|
|
[PubMed: 15286375]
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[Full Text: https://doi.org/10.1126/science.1096621]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ohba, C., Haginoya, K., Osaka, H., Kubota, K., Ishiyama, A., Hiraide, T., Komaki, H., Sasaki, M., Miyatake, S., Nakashima, M., Tsurusaki, Y., Miyake, N., Tanaka, F., Saitsu, H., Matsumoto, N.
|
|
<strong>De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.</strong>
|
|
J. Hum. Genet. 60: 739-742, 2015.
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|
|
|
|
|
[PubMed: 26354034]
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|
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[Full Text: https://doi.org/10.1038/jhg.2015.108]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Okada, Y., Higuchi, H., Hirokawa, N.
|
|
<strong>Processivity of the single-headed kinesin KIF1A through biased binding to tubulin.</strong>
|
|
Nature 424: 574-577, 2003.
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|
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|
|
|
[PubMed: 12891363]
|
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|
|
[Full Text: https://doi.org/10.1038/nature01804]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Okada, Y., Yamazaki, H., Sekine-Aizawa, Y., Hirokawa, N.
|
|
<strong>The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors.</strong>
|
|
Cell 81: 769-780, 1995.
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|
|
[PubMed: 7539720]
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[Full Text: https://doi.org/10.1016/0092-8674(95)90538-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Okamoto, N., Miya, F., Tsunoda, T., Yanagihara, K., Kato, M., Saitoh, S., Yamasaki, M., Kanemura, Y., Kosai, K.
|
|
<strong>KIF1A mutation in a patient with progressive neurodegeneration.</strong>
|
|
J. Hum. Genet. 59: 639-641, 2014.
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|
|
[PubMed: 25253658]
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[Full Text: https://doi.org/10.1038/jhg.2014.80]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others.
|
|
<strong>KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.</strong>
|
|
Europ. J. Hum. Genet. 28: 40-49, 2020.
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|
|
[PubMed: 31488895]
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[Full Text: https://doi.org/10.1038/s41431-019-0497-z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Riviere, J.-B., Ramalingam, S., Lavastre, V., Shekarabi, M., Holbert, S., Lafontaine, J., Srour, M., Merner, N., Rochefort, D., Hince, P., Gaudet, R., Mes-Masson, A.-M., and 11 others.
|
|
<strong>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.</strong>
|
|
Am. J. Hum. Genet. 89: 219-230, 2011.
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|
|
[PubMed: 21820098]
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Stucchi, R., Plucinska, G., Hummel, J. J. A., Zahavi, E. E., Guerra San Juan, I., Klykov, O., Scheltema, R. A., Maarten Altelaar, A. F., Hoogenraad, C. C.
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<strong>Regulation of KIF1A-driven dense core vesicle transport: Ca(2+)/CaM controls DCV binding and liprin-alpha/TANC2 recruits DCVs to postsynaptic sites.</strong>
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Tomishige, M., Klopfenstein, D. R., Vale, R. D.
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<strong>Conversion of Unc104/KIF1A kinesin into a processive motor after dimerization.</strong>
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Van Beusichem, A. E., Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M. A., Kamsteeg, E. J., Stumpel, C., Vermeulen, R. J.
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Bao Lige - updated : 01/11/2021<br>Bao Lige - updated : 08/06/2020<br>Cassandra L. Kniffin - updated : 04/15/2020<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Cassandra L. Kniffin - updated : 8/8/2012<br>Matthew B. Gross - updated : 6/21/2012<br>Ada Hamosh - updated : 9/23/2011<br>Cassandra L. Kniffin - updated : 9/15/2011<br>Ada Hamosh - updated : 8/30/2004<br>Ada Hamosh - updated : 7/31/2003<br>Ada Hamosh - updated : 11/13/2002<br>Stylianos E. Antonarakis - updated : 5/13/2002<br>Ada Hamosh - updated : 5/22/2001<br>Stylianos E. Antonarakis - updated : 2/8/2000<br>Victor A. McKusick - updated : 4/26/1999
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