4766 lines
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Entry
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- *606439 - ATLASTIN GTPase 1; ATL1
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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">*606439</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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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/606439">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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<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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<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=ENSG00000198513;t=ENST00000358385" 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=51062" 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=606439" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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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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<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=ENSG00000198513;t=ENST00000358385" 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_001127713,NM_015915,NM_181598,XM_047431430" 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_015915" 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=606439" 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=05918&isoform_id=05918_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/ATL1" 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/4406632,17226670,18642980,19923445,34189960,37999727,48146423,50949542,51982113,62898433,74024917,119586109,119586110,119586111,119586112,119586113,158261393,189181742,957951071,957951074,957951077,957951080,2217297607,2462540458,2462540460,2462540462" 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/Q8WXF7" 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=51062" 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=ENSG00000198513;t=ENST00000358385" 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=ATL1" 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=ATL1" 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+51062" 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/ATL1" 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:51062" 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/51062" 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=chr14&hgg_gene=ENST00000358385.12&hgg_start=50533082&hgg_end=50633068&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 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/genes/HGNC:11231" 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=606439[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=606439[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/ATL1/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/ENSG00000198513" 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=ATL1" 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=ATL1" 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=ATL1" 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=ATL1&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/PA36061" 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:11231" 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/FBgn0039213.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:1921241" 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/ATL1#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:1921241" 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/51062/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=51062" 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=WBGene00021868;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-8003" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=ATL1&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> 782670003<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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606439
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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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ATLASTIN GTPase 1; ATL1
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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>
|
|
<span class="mim-font">
|
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ATLASTIN<br />
|
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SPG3A GENE; SPG3A
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATL1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATL1</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/14/225?start=-3&limit=10&highlight=225">14q22.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:50533082-50633068&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'})">14:50,533,082-50,633,068</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<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=613708,182600" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</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>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/225?start=-3&limit=10&highlight=225">
|
|
14q22.1
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Neuropathy, hereditary sensory, type ID
|
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613708"> 613708 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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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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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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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">
|
|
Spastic paraplegia 3A, autosomal dominant
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/182600"> 182600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
|
</td>
|
|
</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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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606439" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>The ATL1 gene encodes atlastin-1, a dynamin-related GTPase, which plays a role in formation of the tubular endoplasmic reticulum (ER) network and in axon elongation in neurons (<a href="#23" class="mim-tip-reference" title="Zhu, P.-P., Soderblom, C., Tao-Cheng, J.-H., Stadler, J., Blackstone, C. <strong>SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.</strong> Hum. Molec. Genet. 15: 1343-1353, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537571</a>] [<a href="https://doi.org/10.1093/hmg/ddl054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537571">Zhu et al., 2006</a>; <a href="#15" class="mim-tip-reference" title="Orso, G., Pendin, D., Liu, S., Tosetto, J., Moss, T. J., Faust, J. E., Micaroni, M., Egorova, A., Martinuzzi, A., McNew, J. A., Daga, A. <strong>Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin.</strong> Nature 460: 978-983, 2009. Note: Erratum: Nature 464: 942 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633650</a>] [<a href="https://doi.org/10.1038/nature08280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633650">Orso et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16537571+19633650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning, <a href="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> demonstrated that a form of autosomal dominant hereditary spastic paraplegia with early onset (SPG3A; <a href="/entry/182600">182600</a>), before the age of 10 years and usually before the age of 5, is caused by mutation in a GTPase gene. The gene was found to have no homology to genes that cause other forms of hereditary spastic paraplegia. It does show significant homology to guanylate binding protein-1 (GBP1; <a href="/entry/600411">600411</a>), a member of the dynamin family of large GTPases. Northern blot analysis of ATL1 expression detected a 2.2-kb transcript primarily in adult and fetal brain. RT-PCR experiments indicated measurable expression in all tissues examined, although expression in adult brain was at least 50-fold higher than in other tissues. Translation of the 2.2-kb cDNA sequence of ATL1 yielded a peptide of 558 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR of a cerebral cortex cDNA library, <a href="#22" class="mim-tip-reference" title="Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C. <strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong> J. Biol. Chem. 278: 49063-49071, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506257</a>] [<a href="https://doi.org/10.1074/jbc.M306702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506257">Zhu et al. (2003)</a> cloned ATL1, which they called atlastin-1. The deduced 558-amino acid protein contains GTP-binding motifs in its N-terminal half and 2 transmembrane domains in its C-terminal half. It also has 3 potential N-glycosylation sites. Western blot analysis of transfected COS-7 cells detected atlastin-1 at an apparent molecular mass of about 64 kD. Western blot analysis detected high atlastin-1 expression in human and rat brain homogenates, with much lower expression in several other human tissues, including smooth muscle, adrenal gland, kidney, testis, and lung. Immunohistochemical analysis of rat brain sections detected high expression of atlastin-1 in cortical neurons of lamina V, pyramidal neurons in CA1 and CA3 of the hippocampus, and in amygdala and several thalamic nuclei. Staining was most prominent in the cell soma, with weaker staining of axons and dendrites. Immunogold labeling detected rat atlastin-1 predominantly in the cis-Golgi cisternae. Protease protection assays indicated that the N and C termini of human atlastin-1 were exposed to the cytoplasmic face of the membrane in transfected cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a yeast 2-hybrid assay, <a href="#22" class="mim-tip-reference" title="Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C. <strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong> J. Biol. Chem. 278: 49063-49071, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506257</a>] [<a href="https://doi.org/10.1074/jbc.M306702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506257">Zhu et al. (2003)</a> determined that atlastin-1 self-associates. Chemical cross-linking experiments indicated that atlastin-1 most likely forms a homotetramer of about 230 kD. <a href="#22" class="mim-tip-reference" title="Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C. <strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong> J. Biol. Chem. 278: 49063-49071, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506257</a>] [<a href="https://doi.org/10.1074/jbc.M306702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506257">Zhu et al. (2003)</a> demonstrated that atlastin-1 has GTPase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Independently, <a href="#6" class="mim-tip-reference" title="Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B., Lauring, B. <strong>Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance.</strong> Proc. Nat. Acad. Sci. 103: 10666-10671, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16815977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16815977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16815977[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.0510863103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16815977">Evans et al. (2006)</a> and <a href="#18" class="mim-tip-reference" title="Sanderson, C. M., Connell, J. W., Edwards, T. L., Bright, N. A., Duley, S., Thompson, A., Luzio, J. P., Reid, E. <strong>Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners.</strong> Hum. Molec. Genet. 15: 307-318, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16339213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16339213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16339213[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16339213">Sanderson et al. (2006)</a> demonstrated that the N-terminal domain of spastin (SPAST; <a href="/entry/604277">604277</a>) bound directly to the C-terminal cytoplasmic domain of atlastin, suggesting that the 2 gene products interact in a common biologic pathway. <a href="#6" class="mim-tip-reference" title="Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B., Lauring, B. <strong>Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance.</strong> Proc. Nat. Acad. Sci. 103: 10666-10671, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16815977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16815977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16815977[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.0510863103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16815977">Evans et al. (2006)</a> used yeast 2-hybrid analysis and coimmunoprecipitation studies in HeLa cells, and <a href="#18" class="mim-tip-reference" title="Sanderson, C. M., Connell, J. W., Edwards, T. L., Bright, N. A., Duley, S., Thompson, A., Luzio, J. P., Reid, E. <strong>Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners.</strong> Hum. Molec. Genet. 15: 307-318, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16339213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16339213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16339213[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16339213">Sanderson et al. (2006)</a> used yeast 2-hybrid analysis of a human fetal brain cDNA library and protein pull-down, coimmunoprecipitation, and colocalization studies in HeLa cells, HEK293T cells, and mouse NSC34 neuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16815977+16339213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the developing rat brain, <a href="#23" class="mim-tip-reference" title="Zhu, P.-P., Soderblom, C., Tao-Cheng, J.-H., Stadler, J., Blackstone, C. <strong>SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.</strong> Hum. Molec. Genet. 15: 1343-1353, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537571</a>] [<a href="https://doi.org/10.1093/hmg/ddl054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537571">Zhu et al. (2006)</a> found that atlastin-1 was expressed not only in the Golgi apparatus and endoplasmic reticulum, but was also enriched in axonal growth cones and growth cone-like varicosities along the axons. Atlastin-1 labeling was prominent on vesicular structures within the growth cones, but not at the plasma membrane and not at synapses. Knockdown of atlastin-1 using shRNA in cultured cortical cells inhibited axonal growth. Overall, the findings suggested that atlastin-1 has diverse functions in neurons, likely acting both in intracellular membrane trafficking as well as in expansion at the axonal growth cone. These functional studies suggested that the early-onset axonopathy observed in SPG3A may result from abnormal development of axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Orso, G., Pendin, D., Liu, S., Tosetto, J., Moss, T. J., Faust, J. E., Micaroni, M., Egorova, A., Martinuzzi, A., McNew, J. A., Daga, A. <strong>Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin.</strong> Nature 460: 978-983, 2009. Note: Erratum: Nature 464: 942 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633650</a>] [<a href="https://doi.org/10.1038/nature08280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633650">Orso et al. (2009)</a> demonstrated that Drosophila atlastin localizes on endoplasmic reticulum (ER) membranes and that its loss causes ER fragmentation. Drosophila atlastin embedded in distinct membranes has the ability to form trans-oligomeric complexes, and its overexpression induces enlargement of ER profiles, consistent with excessive fusion of ER membranes. In vitro experiments confirmed that atlastin autonomously drives membrane fusion in a GTP-dependent fashion. In contrast, GTPase-deficient atlastin is inactive, unable to form trans-oligomeric complexes owing to failure to self-associate, and incapable of promoting fusion in vitro. The results of <a href="#15" class="mim-tip-reference" title="Orso, G., Pendin, D., Liu, S., Tosetto, J., Moss, T. J., Faust, J. E., Micaroni, M., Egorova, A., Martinuzzi, A., McNew, J. A., Daga, A. <strong>Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin.</strong> Nature 460: 978-983, 2009. Note: Erratum: Nature 464: 942 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633650</a>] [<a href="https://doi.org/10.1038/nature08280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633650">Orso et al. (2009)</a> demonstrated that atlastin mediates membrane tethering and fusion and strongly suggested that it is the GTPase activity required for ER homotypic fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19633650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> found that the ATL1 gene contains 14 exons and spans approximately 69 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> determined that the ATL1 gene maps to chromosome 14q11-q21. <a href="#22" class="mim-tip-reference" title="Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C. <strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong> J. Biol. Chem. 278: 49063-49071, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506257</a>] [<a href="https://doi.org/10.1074/jbc.M306702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506257">Zhu et al. (2003)</a> stated that the ATL1 gene maps to chromosome 14q22.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14506257+11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3A</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> identified mutations in the ATL1 gene (see, e.g., <a href="#0001">606439.0001</a>) in families with spastic paraplegia-3A (SPG3A; <a href="/entry/182600">182600</a>) in which linkage to 14q11-q21 had been demonstrated as well as in other phenotypically similar families without linkage evidence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Durr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Rossi, A., Gil, R., Rousselle, C., Ruberg, M., Stevanin, G., Brice, A. <strong>Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.</strong> Arch. Neurol. 61: 1867-1872, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15596607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15596607</a>] [<a href="https://doi.org/10.1001/archneur.61.12.1867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15596607">Durr et al. (2004)</a> identified mutations in the ATL1 gene in 12 (39%) of 31 families with early-onset autosomal dominant spastic paraplegia. One family showed incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15596607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Namekawa, M., Ribai, P., Nelson, I., Forlani, S., Fellmann, F., Goizet, C., Depienne, C., Stevanin, G., Ruberg, M., Durr, A., Brice, A. <strong>SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.</strong> Neurology 66: 112-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401858</a>] [<a href="https://doi.org/10.1212/01.wnl.0000191390.20564.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16401858">Namekawa et al. (2006)</a> stated that 19 mutations in the ATL1 gene had been identified in 40 different families. More than 90% of the mutations were located in exons 4 (12.5%), 7 (27.5%), 8 (17.5%), and 12 (35%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 COS-7 cells, <a href="#23" class="mim-tip-reference" title="Zhu, P.-P., Soderblom, C., Tao-Cheng, J.-H., Stadler, J., Blackstone, C. <strong>SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.</strong> Hum. Molec. Genet. 15: 1343-1353, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537571</a>] [<a href="https://doi.org/10.1093/hmg/ddl054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537571">Zhu et al. (2006)</a> showed that disease-associated missense mutations in the ATL1 gene were expressed and interacted strongly with wildtype ATL1, causing a decrease in GTPase activity in a dominant-negative manner. The GTPase impairment was strongest with the R217Q mutation (<a href="#0004">606439.0004</a>), which is located within the GTPase binding site, but was also observed with other missense mutations (R239C; <a href="#0001">606439.0001</a> and H258R; <a href="#0003">606439.0003</a>), suggesting that these regions may modulate activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Beetz, C., Nygren, A. O. H., Deufel, T., Reid, E. <strong>An SPG3A whole gene deletion neither co-segregates with disease nor modifies phenotype in a hereditary spastic paraplegia family with a pathogenic SPG4 mutation. (Letter)</strong> Neurogenetics 8: 317-318, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17657515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17657515</a>] [<a href="https://doi.org/10.1007/s10048-007-0099-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17657515">Beetz et al. (2007)</a> reported a family in which spastic paraplegia segregated with a deletion of exon 1 of the SPAST gene (<a href="/entry/604277">604277</a>) in the proband, her brother, and her 2 sons. Although the proband and her brother also had a deletion of the ATL1 gene, the ATL1 deletion did not segregate with the disorder in her sons and had no apparent effect on the severity of the disorder. The findings suggested that haploinsufficiency is the pathogenic mechanism for SPG4 (<a href="/entry/182601">182601</a>), whereas a dominant-negative effect is the pathogenic mechanism for SPG3A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17657515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1D</em></strong></p><p>
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By genomewide linkage analysis followed by array-based exonic sequencing of candidate genes, <a href="#7" class="mim-tip-reference" title="Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M. <strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong> Am. J. Hum. Genet. 88: 99-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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.2010.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21194679">Guelly et al. (2011)</a> identified a heterozygous mutation in the ATL1 gene (N355K; <a href="#0010">606439.0010</a>) as a cause of autosomal dominant hereditary neuropathy type 1D (HSN1D; <a href="/entry/613708">613708</a>) in an affected family. Screening of this gene in 115 additional probands with a similar disorder identified 2 additional heterozygous mutations in the ATL1 gene in 2 unrelated probands (<a href="#0011">606439.0011</a> and <a href="#0012">606439.0012</a>, respectively). The phenotype was characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients showed features suggesting upper neuron involvement. In vitro functional expression studies in COS-7 cells did not reveal a common pathogenetic mechanism, and there was no clear functional distinction between mutations causing SPG3A and HSN1D, but <a href="#7" class="mim-tip-reference" title="Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M. <strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong> Am. J. Hum. Genet. 88: 99-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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.2010.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21194679">Guelly et al. (2011)</a> postulated that a defect in the tubular endoplasmic reticulum may underlie both disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21194679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=606439[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In affected members of 3 apparently unrelated kindreds with spastic paraplegia-3 (<a href="/entry/182600">182600</a>), <a href="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> identified a heterozygous 884C-T transition in exon 7 of the ATL1 gene, resulting in an arg239-to-cys (R239C) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abel, A., Fonknechten, N., Hofer, A., Durr, A., Cruaud, C., Voit, T., Weissenbach, J., Brice, A., Klimpe, S., Auburger, G., Hazan, J. <strong>Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.</strong> Neurogenetics 5: 239-243, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15517445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15517445</a>] [<a href="https://doi.org/10.1007/s10048-004-0191-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15517445">Abel et al. (2004)</a> identified the R239C mutation in all 22 affected members of a French family with SPG3 reported by <a href="#8" class="mim-tip-reference" title="Hazan, J., Lamy, C., Melki, J., Munnich, A., de Recondo, J., Weissenbach, J. <strong>Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q.</strong> Nature Genet. 5: 163-167, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8252041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8252041</a>] [<a href="https://doi.org/10.1038/ng1093-163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8252041">Hazan et al. (1993)</a>. <a href="#1" class="mim-tip-reference" title="Abel, A., Fonknechten, N., Hofer, A., Durr, A., Cruaud, C., Voit, T., Weissenbach, J., Brice, A., Klimpe, S., Auburger, G., Hazan, J. <strong>Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.</strong> Neurogenetics 5: 239-243, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15517445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15517445</a>] [<a href="https://doi.org/10.1007/s10048-004-0191-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15517445">Abel et al. (2004)</a> stated that this was the seventh SPG3 family of western European descent found to have the R239C mutation. <a href="#1" class="mim-tip-reference" title="Abel, A., Fonknechten, N., Hofer, A., Durr, A., Cruaud, C., Voit, T., Weissenbach, J., Brice, A., Klimpe, S., Auburger, G., Hazan, J. <strong>Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.</strong> Neurogenetics 5: 239-243, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15517445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15517445</a>] [<a href="https://doi.org/10.1007/s10048-004-0191-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15517445">Abel et al. (2004)</a> reported the nucleotide change as 715C-T, based on numbering from the translation initiation codon, and noted that position 715 is within a CpG doublet, suggesting that it is a possible mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15517445+8252041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By haplotype analysis of 3 French families with the R239C mutation, <a href="#12" class="mim-tip-reference" title="Namekawa, M., Nelson, I., Ribai, P., Durr, A., Denis, E., Stevanin, G., Ruberg, M., Brice, A. <strong>A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. (Letter)</strong> Neurogenetics 7: 131-132, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16612642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16612642</a>] [<a href="https://doi.org/10.1007/s10048-006-0028-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16612642">Namekawa et al. (2006)</a> concluded that the mutations arose independently and were not due to a founder effect. Further analysis confirmed that the mutation occurred in a hotspot defined by a methylated CpG dinucleotide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16612642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs119476047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119476047;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=rs119476047" 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=rs119476047" 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=RCV000004595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004595</a>
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<p>In a kindred designated ADHSP-P with early-onset autosomal dominant spastic paraplegia (<a href="/entry/182600">182600</a>), <a href="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> identified heterozygosity (both C and A) at nucleotide 945 of the full-length ATL1 cDNA, corresponding to exon 8 of the gene. Unaffected members of the family had only C at this position. This mutation, TCC (ser) to TAC (tyr), was predicted to alter amino acid 259. Thus, this mutation, S259Y, is adjacent to the H258R mutation (<a href="#0003">606439.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
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ATL1, HIS258ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119476048 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119476048;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=rs119476048" 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=rs119476048" 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=RCV000004596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004596</a>
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<p><a href="#21" class="mim-tip-reference" title="Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K. <strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong> Nature Genet. 29: 326-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>] [<a href="https://doi.org/10.1038/ng758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11685207">Zhao et al. (2001)</a> found that affected members in a kindred with autosomal dominant hereditary spastic paraplegia of early onset (<a href="/entry/182600">182600</a>) were heterozygous (A and G) at nucleotide position 942 of the full-length cDNA corresponding to the ATL1 gene. Affected members in this kindred had only C at this position. The mutation was predicted to result in a his258-to-arg (H258R) amino acid substitution, at a site adjacent to S259Y (<a href="#0002">606439.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
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ATL1, ARG217GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119476049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119476049;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=rs119476049" 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=rs119476049" 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=RCV000004597 OR RCV001725929" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004597, RCV001725929" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004597...</a>
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<p>In a large Italian family with early-onset, autosomal dominant uncomplicated spastic paraplegia (<a href="/entry/182600">182600</a>), <a href="#11" class="mim-tip-reference" title="Muglia, M., Magariello, A., Nicoletti, G., Patitucci, A., Gabriele, A. L., Conforti, F. L., Mazzei, R., Caracciolo, M., Ardito, B., Lastilla, M., Tedeschi, G., Quattrone, A. <strong>Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia.</strong> Ann. Neurol. 51: 794-795, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112092</a>] [<a href="https://doi.org/10.1002/ana.10185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112092">Muglia et al. (2002)</a> identified an 818G-A mutation in the ATL1 gene, resulting in an arg217-to-gln substitution in a highly conserved GTPase motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
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ATL1, 1-BP INS, 1688A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223314;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=rs863223314" 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=rs863223314" 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=RCV000020718" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020718" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020718</a>
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<p>In an Italian family with autosomal dominant hereditary spastic paraplegia (<a href="/entry/182600">182600</a>), <a href="#19" class="mim-tip-reference" title="Tessa, A., Casali, C., Damiano, M., Bruno, C., Fortini, D., Patrono, C., Cricchi, F., Valoppi, M., Nappi, G., Amabile, G. A., Bertini, E., Santorelli, F. M. <strong>SPG3A: an additional family carrying a new atlastin mutation.</strong> Neurology 59: 2002-2005, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499504</a>] [<a href="https://doi.org/10.1212/01.wnl.0000036902.21438.98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499504">Tessa et al. (2002)</a> identified a heterozygous 1-bp insertion, 1688A, in exon 12 of the ATL1 gene, producing a frameshift and premature stop codon. The resulting protein lacked the last 37 amino acids, including all of exon 14. Seven clearly affected individuals and 2 asymptomatic individuals with hyperreflexia carried the mutation. The authors commented on the apparent age-dependent penetrance of the disorder in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
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ATL1, MET408VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28939094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939094;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=rs28939094" 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=rs28939094" 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=RCV000004599" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004599" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004599</a>
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<p>In a family with 6 members affected with a very early onset severe form of spastic paraplegia (<a href="/entry/182600">182600</a>), <a href="#4" class="mim-tip-reference" title="Dalpozzo, F., Rossetto, M. G., Boaretto, F., Sartori, E., Mostacciuolo, M. L., Daga, A., Bassi, M. T., Martinuzzi, A. <strong>Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation.</strong> Neurology 61: 580-581, 2003. Note: Erratum: Neurology 62: 348 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939451</a>] [<a href="https://doi.org/10.1212/01.wnl.0000078189.73611.df" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939451">Dalpozzo et al. (2003)</a> identified a heterozygous 1222A-G transition in exon 12 of the ATL1 gene, resulting in a met408-to-val (M408V) substitution. All affected members had onset in infancy with delayed motor milestones, gait impairment, spastic paraparesis, distal atrophy, and lower limb weakness. Because of the very early onset, the first patients were misdiagnosed with cerebral palsy, and the index patient (mother of 5 affected members) was unaware that she had a genetically transmissible disease. Two patients had the unusual sign of mild hand atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<strong>.0007 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</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> rs119476050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119476050;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/rs119476050?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=rs119476050" 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=rs119476050" 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=RCV000004600 OR RCV000190652 OR RCV001090532" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004600, RCV000190652, RCV001090532" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004600...</a>
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<p>In all 3 affected members tested from an Italian family with SPG3A (<a href="/entry/182600">182600</a>), <a href="#3" class="mim-tip-reference" title="D'Amico, A., Tessa, A., Sabino, A., Bertini, E., Santorelli, F. M., Servidei, S. <strong>Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.</strong> Neurology 62: 2138-2139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127698.88895.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184642">D'Amico et al. (2004)</a> identified a heterozygous mutation in exon 12 of the atlastin gene, resulting in an arg415-to-trp (R415W) substitution. The mutation was not identified in 400 control chromosomes. The 3 patients had onset before 5 years of age, and 2 additional family members were reportedly affected by infantile-onset spastic paraparesis. However, 9 asymptomatic relatives ranging in age from 13 to 70 years also had the mutation. <a href="#3" class="mim-tip-reference" title="D'Amico, A., Tessa, A., Sabino, A., Bertini, E., Santorelli, F. M., Servidei, S. <strong>Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.</strong> Neurology 62: 2138-2139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127698.88895.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184642">D'Amico et al. (2004)</a> concluded that the reduced penetrance of this mutation indicated that modulator genes or epigenetic factors are involved in the development of the disease, and they noted the implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> identified a heterozygous c.1243C-T transition in the ATL1 gene resulting in an R415W substitution in affected members of a family with SPG3A originally reported by <a href="#16" class="mim-tip-reference" title="Raggio, J. F., Thurmon, T. F., Anderson, E. E. <strong>X-linked hereditary spastic paraplegia.</strong> J. La. State Med. Soc. 125: 4-6, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4684346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4684346</a>]" pmid="4684346">Raggio et al. (1973)</a> as having a pure spastic paraplegia transmitted in an X-linked pattern of inheritance. Whole-exome sequencing of 1 of the affected males identified the heterozygous R415W substitution. This mutation was then identified in 3 affected family members and in 3 unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families. <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> also identified a heterozygous c.1244A-G transition, resulting in an arg415-to-gln (R415Q; <a href="#0014">606439.0014</a>) substitution, in a Moroccan family with SPG3A and incomplete penetrance. <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 affects a highly conserved residue that does not localize to a known protein domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23483706+4684346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs119476051 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119476051;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=rs119476051" 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=rs119476051" 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=RCV000004601" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004601" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004601</a>
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<p>In a mother and son with SPG3A (<a href="/entry/182600">182600</a>), <a href="#17" class="mim-tip-reference" title="Rainier, S., Sher, C., Reish, O., Thomas, D., Fink, J. K. <strong>De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.</strong> Arch. Neurol. 63: 445-447, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16533974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16533974</a>] [<a href="https://doi.org/10.1001/archneur.63.3.445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16533974">Rainier et al. (2006)</a> identified a heterozygous 638T-C transition in exon 4 of the ATL1 gene, resulting in a leu157-to-trp (L157W) substitution. The mutation is predicted to disrupt a putative phosphorylation site of the protein. Genetic analysis of family members indicated that the mutation occurred de novo in the mother. The mother was a 34-year-old woman with uncomplicated nonprogressive spastic paraplegia since infancy who was originally diagnosed with spastic diplegic cerebral palsy. She was correctly diagnosed with SPG after her son developed similar clinical symptoms at age 10 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1595625206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1595625206;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=rs1595625206" 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=rs1595625206" 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=RCV000004602 OR RCV001847580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004602, RCV001847580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004602...</a>
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<p>In affected members of a large French Canadian family with SPG3A (<a href="/entry/182600">182600</a>), <a href="#10" class="mim-tip-reference" title="Meijer, I. A., Dion, P., Laurent, S., Dupre, N., Brais, B., Levert, A., Puymirat, J., Rioux, M. F., Sylvain, M., Zhu, P.-P., Soderblom, C., Stadler, J., Blackstone, C., Rouleau, G. A. <strong>Characterization of a novel SPG3A deletion in a French-Canadian family.</strong> Ann. Neurol. 61: 599-603, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17427918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17427918</a>] [<a href="https://doi.org/10.1002/ana.21114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17427918">Meijer et al. (2007)</a> identified a heterozygous 3-bp in-frame deletion in the ATL1 gene, resulting in a deletion of asn436 (436delN). Functional expression studies showed decreased ATL1 protein levels in patients' lymphoblasts but normal levels of mRNA, normal GTPase activity, and normal protein interactions. <a href="#10" class="mim-tip-reference" title="Meijer, I. A., Dion, P., Laurent, S., Dupre, N., Brais, B., Levert, A., Puymirat, J., Rioux, M. F., Sylvain, M., Zhu, P.-P., Soderblom, C., Stadler, J., Blackstone, C., Rouleau, G. A. <strong>Characterization of a novel SPG3A deletion in a French-Canadian family.</strong> Ann. Neurol. 61: 599-603, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17427918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17427918</a>] [<a href="https://doi.org/10.1002/ana.21114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17427918">Meijer et al. (2007)</a> postulated decreased protein stability and a dominant-negative loss-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17427918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 NEUROPATHY, HEREDITARY SENSORY, TYPE ID</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">rs1555365597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555365597;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=rs1555365597" 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=rs1555365597" 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=RCV000023542 OR RCV000626932 OR RCV000789726" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023542, RCV000626932, RCV000789726" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023542...</a>
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<p>In affected members of a large 4-generation family with autosomal dominant hereditary sensory neuropathy type ID (HSN1D; <a href="/entry/613708">613708</a>), <a href="#7" class="mim-tip-reference" title="Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M. <strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong> Am. J. Hum. Genet. 88: 99-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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.2010.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21194679">Guelly et al. (2011)</a> identified a heterozygous 1065C-A transversion in exon 11 of the ATL1 gene, resulting in an asn355-to-lys (N355K) substitution. The mutation was not found in 370 controls. The phenotype was characterized by early adult onset of a severe distal st sensory axonal neuropathy with frequent ulcerations and amputation digits. In vitro functional expression studies in COS-7 cells showed that the mutant protein had decreased GTPase activity compared to wildtype, and caused disruption of endoplasmic reticulum 3-way junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21194679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs200314808 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200314808;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/rs200314808?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=rs200314808" 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=rs200314808" 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=RCV000023543 OR RCV000236565 OR RCV000543629 OR RCV002415427" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023543, RCV000236565, RCV000543629, RCV002415427" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023543...</a>
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<p>In a 61-year-old man with hereditary sensory neuropathy-1D (HSN1D; <a href="/entry/613708">613708</a>), <a href="#7" class="mim-tip-reference" title="Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M. <strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong> Am. J. Hum. Genet. 88: 99-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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.2010.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21194679">Guelly et al. (2011)</a> identified a heterozygous 196G-C transversion in exon 2 of the ATL1 gene, resulting in a glu66-to-gln (E66Q) substitution. He presented with progressive, ascending, severe sensory loss affecting all modalities in the lower legs, but no foot ulcerations or paresis. He had hyporeflexia, and sural nerve biopsy revealed a severe, chronic, axonal neuropathy with a moderate demyelinating component. The patient's deceased mother reportedly had a similar severe sensory neuropathy. The mutation was not found in 150 control individuals, but in vitro functional expression studies showed no change in GTPase activity and no changes in endoplasmic reticulum morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21194679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1595619553 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1595619553;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=rs1595619553" 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=rs1595619553" 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=RCV000023544 OR RCV000789725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023544, RCV000789725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023544...</a>
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<p>In a man with hereditary sensory neuropathy-1D (HSN1D; <a href="/entry/613708">613708</a>), <a href="#7" class="mim-tip-reference" title="Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M. <strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong> Am. J. Hum. Genet. 88: 99-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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.2010.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21194679">Guelly et al. (2011)</a> identified a heterozygous 1-bp deletion (976delG) in exon 9 of the ATL1 gene, resulting in premature termination in the C terminus. The patient had adult-onset sensory neuropathy with ulcerations, lack of pain perception, paresthesias in the fingers, and occasional lancinating pains in his ankles. Patellar tendon reflexes were brisk, and Achilles tendon reflexes were absent. His father and brother were similarly affected. The mutation was not found in 334 control individuals. In vitro functional expression studies showed decreased expression of the truncated protein and diffuse localization throughout the cytoplasm instead of proper localization to the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21194679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</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> rs387906941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906941;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/rs387906941?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=rs387906941" 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=rs387906941" 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=RCV000023545 OR RCV001847621 OR RCV002285257 OR RCV002513195 OR RCV004767019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023545, RCV001847621, RCV002285257, RCV002513195, RCV004767019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023545...</a>
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<p>In affected members of a 3-generation South African Zulu family with autosomal dominant SPG3A (<a href="/entry/182600">182600</a>), <a href="#14" class="mim-tip-reference" title="Orlacchio, A., Montieri, P., Babalini, C., Gaudiello, F., Bernardi, G., Kawarai, T. <strong>Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation. (Letter)</strong> J. Neurol. 258: 1361-1363, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21336785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21336785</a>] [<a href="https://doi.org/10.1007/s00415-011-5934-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21336785">Orlacchio et al. (2011)</a> identified a heterozygous 1246C-T transition in exon 12 of the ATL1 gene, resulting in an arg416-to-cys (R416C) substitution. The mutation was not found in 400 controls. The phenotype in this family was unusual in that affected individuals had late onset (range 38 to 56 years), mild mental retardation (IQ 32 to 67), and thin corpus callosum without cerebellar involvement or white matter abnormalities. Spasticity was restricted to the lower limbs; 3 patients had sphincter disturbances. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21336785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs397514712 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514712;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/rs397514712?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=rs397514712" 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=rs397514712" 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=RCV000050231 OR RCV000480817" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000050231, RCV000480817" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000050231...</a>
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<p>In 4 Moroccan sibs with SPG3A (<a href="/entry/182600">182600</a>), <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> identified a c.1244A-G transition in the ATL1 gene, resulting in an arg415-to-gln (R415Q) substitution. Three sibs were homozygous and 1 was heterozygous for the mutation. Heterozygosity for the mutation was then found in 3 unaffected family members and in 2 family members who had very subtle signs of the disorder (hyperreflexia). These findings suggested complete penetrance for the mutation in homozygous state and incomplete penetrance for the mutation in heterozygous state. <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> also identified a heterozygous c.1243C-T transition, resulting in an R415W (<a href="#0007">606439.0007</a>) substitution in another family with SPG3A and incomplete penetrance. <a href="#20" class="mim-tip-reference" title="Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. <strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong> Hum. Mutat. 34: 860-863, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>] [<a href="https://doi.org/10.1002/humu.22309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23483706">Varga et al. (2013)</a> noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 is a highly conserved residue that does not localize to a known protein domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23483706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs606231265 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231265;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/rs606231265?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=rs606231265" 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=rs606231265" 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=RCV000144894 OR RCV000281684 OR RCV002514782" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144894, RCV000281684, RCV002514782" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144894...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to an autosomal recessive form of SPG3A (see <a href="/entry/182600">182600</a>) has not been confirmed.</p><p>In 6 males from a large Pakistani family with SPG3A, <a href="#9" class="mim-tip-reference" title="Khan, T. N., Klar, J., Tariq, M., Anjum Baig, S., Malik, N. A., Yousaf, R., Baig, S. M., Dahl, N. <strong>Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.</strong> Europ. J. Hum. Genet. 22: 1180-1184, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24473461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24473461</a>] [<a href="https://doi.org/10.1038/ejhg.2014.5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24473461">Khan et al. (2014)</a> identified a homozygous c.353G-A transition in exon 4 of the ATL1 gene, resulting in an arg118-to-gln (R118Q) substitution at a highly conserved residue in the GTPase domain. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Variant Server database or in 200 Pakistani control chromosomes. Functional studies of the variant were not performed. The affected males who were homozygous for the variant presented with pure SPG before 2 years of age. Seven family members were heterozygous for the variant, all of whom were asymptomatic except for 1 woman who had subclinically reduced vibration sensation. <a href="#9" class="mim-tip-reference" title="Khan, T. N., Klar, J., Tariq, M., Anjum Baig, S., Malik, N. A., Yousaf, R., Baig, S. M., Dahl, N. <strong>Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.</strong> Europ. J. Hum. Genet. 22: 1180-1184, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24473461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24473461</a>] [<a href="https://doi.org/10.1038/ejhg.2014.5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24473461">Khan et al. (2014)</a> concluded that SPG3A in this family was transmitted in an autosomal recessive pattern, adding to the clinical complexity of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24473461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<strong>Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.</strong>
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[<a href="https://doi.org/10.1007/s10048-004-0191-2" target="_blank">Full Text</a>]
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Beetz, C., Nygren, A. O. H., Deufel, T., Reid, E.
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<strong>An SPG3A whole gene deletion neither co-segregates with disease nor modifies phenotype in a hereditary spastic paraplegia family with a pathogenic SPG4 mutation. (Letter)</strong>
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Neurogenetics 8: 317-318, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17657515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17657515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17657515" 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/10.1007/s10048-007-0099-8" target="_blank">Full Text</a>]
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D'Amico, A., Tessa, A., Sabino, A., Bertini, E., Santorelli, F. M., Servidei, S.
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<strong>Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.</strong>
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Neurology 62: 2138-2139, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000127698.88895.85" target="_blank">Full Text</a>]
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Dalpozzo, F., Rossetto, M. G., Boaretto, F., Sartori, E., Mostacciuolo, M. L., Daga, A., Bassi, M. T., Martinuzzi, A.
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<strong>Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation.</strong>
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Neurology 61: 580-581, 2003. Note: Erratum: Neurology 62: 348 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Durr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Rossi, A., Gil, R., Rousselle, C., Ruberg, M., Stevanin, G., Brice, A.
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<strong>Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.</strong>
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Arch. Neurol. 61: 1867-1872, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15596607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15596607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15596607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B., Lauring, B.
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<strong>Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance.</strong>
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Proc. Nat. Acad. Sci. 103: 10666-10671, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16815977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16815977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16815977[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=16815977" 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/10.1073/pnas.0510863103" target="_blank">Full Text</a>]
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Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M.
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<strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong>
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Am. J. Hum. Genet. 88: 99-105, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21194679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21194679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21194679[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=21194679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.12.003" target="_blank">Full Text</a>]
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Hazan, J., Lamy, C., Melki, J., Munnich, A., de Recondo, J., Weissenbach, J.
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<strong>Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q.</strong>
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Nature Genet. 5: 163-167, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8252041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8252041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8252041" 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/ng1093-163" target="_blank">Full Text</a>]
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Khan, T. N., Klar, J., Tariq, M., Anjum Baig, S., Malik, N. A., Yousaf, R., Baig, S. M., Dahl, N.
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<strong>Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.</strong>
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Europ. J. Hum. Genet. 22: 1180-1184, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24473461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24473461</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24473461" 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.2014.5" target="_blank">Full Text</a>]
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<strong>Characterization of a novel SPG3A deletion in a French-Canadian family.</strong>
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[<a href="https://doi.org/10.1002/ana.21114" target="_blank">Full Text</a>]
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<strong>Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia.</strong>
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[<a href="https://doi.org/10.1002/ana.10185" target="_blank">Full Text</a>]
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<strong>A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. (Letter)</strong>
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[<a href="https://doi.org/10.1007/s10048-006-0028-2" target="_blank">Full Text</a>]
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<a id="Namekawa2006" class="mim-anchor"></a>
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Namekawa, M., Ribai, P., Nelson, I., Forlani, S., Fellmann, F., Goizet, C., Depienne, C., Stevanin, G., Ruberg, M., Durr, A., Brice, A.
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<strong>SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.</strong>
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[<a href="https://doi.org/10.1212/01.wnl.0000191390.20564.8e" target="_blank">Full Text</a>]
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<strong>Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation. (Letter)</strong>
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[<a href="https://doi.org/10.1007/s00415-011-5934-z" target="_blank">Full Text</a>]
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Orso, G., Pendin, D., Liu, S., Tosetto, J., Moss, T. J., Faust, J. E., Micaroni, M., Egorova, A., Martinuzzi, A., McNew, J. A., Daga, A.
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<strong>Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin.</strong>
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[<a href="https://doi.org/10.1038/nature08280" target="_blank">Full Text</a>]
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Rainier, S., Sher, C., Reish, O., Thomas, D., Fink, J. K.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16533974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16533974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533974" 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/10.1001/archneur.63.3.445" target="_blank">Full Text</a>]
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Hum. Molec. Genet. 15: 307-318, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16339213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16339213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16339213[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=16339213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi447" target="_blank">Full Text</a>]
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Tessa, A., Casali, C., Damiano, M., Bruno, C., Fortini, D., Patrono, C., Cricchi, F., Valoppi, M., Nappi, G., Amabile, G. A., Bertini, E., Santorelli, F. M.
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<strong>SPG3A: an additional family carrying a new atlastin mutation.</strong>
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Neurology 59: 2002-2005, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499504</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000036902.21438.98" target="_blank">Full Text</a>]
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Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C.
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<strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong>
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Hum. Mutat. 34: 860-863, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23483706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23483706</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23483706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22309" target="_blank">Full Text</a>]
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<a id="Zhao2001" class="mim-anchor"></a>
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Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K.
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<strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11685207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11685207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11685207" 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/ng758" target="_blank">Full Text</a>]
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Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C.
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<strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M306702200" target="_blank">Full Text</a>]
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Zhu, P.-P., Soderblom, C., Tao-Cheng, J.-H., Stadler, J., Blackstone, C.
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<strong>SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.</strong>
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Hum. Molec. Genet. 15: 1343-1353, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537571</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl054" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/3/2014
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 7/25/2013<br>Cassandra L. Kniffin - updated : 10/11/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Cassandra L. Kniffin - updated : 10/15/2010<br>Patricia A. Hartz - updated : 11/11/2009<br>Ada Hamosh - updated : 9/15/2009<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 11/27/2007<br>Cassandra L. Kniffin - updated : 2/6/2007<br>Cassandra L. Kniffin - updated : 9/1/2006<br>Cassandra L. Kniffin - updated : 8/23/2006<br>Cassandra L. Kniffin - updated : 4/6/2006<br>Cassandra L. Kniffin -updated : 9/26/2005<br>Patricia A. Hartz - updated : 5/12/2005<br>Cassandra L. Kniffin - updated : 4/11/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Cassandra L. Kniffin - updated : 2/19/2003<br>Cassandra L. Kniffin - updated : 8/19/2002
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/2/2001
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/06/2014
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<div class="row collapse" id="mimCollapseEditHistory">
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mcolton : 11/3/2014<br>ckniffin : 11/3/2014<br>carol : 12/16/2013<br>carol : 9/16/2013<br>carol : 7/26/2013<br>ckniffin : 7/25/2013<br>carol : 10/13/2011<br>carol : 10/13/2011<br>carol : 10/13/2011<br>terry : 10/12/2011<br>ckniffin : 10/11/2011<br>wwang : 3/2/2011<br>wwang : 2/23/2011<br>wwang : 2/23/2011<br>ckniffin : 1/28/2011<br>wwang : 10/27/2010<br>ckniffin : 10/15/2010<br>alopez : 6/1/2010<br>mgross : 11/13/2009<br>terry : 11/11/2009<br>alopez : 9/15/2009<br>terry : 9/15/2009<br>wwang : 1/15/2008<br>ckniffin : 12/27/2007<br>wwang : 12/4/2007<br>ckniffin : 11/27/2007<br>wwang : 2/8/2007<br>ckniffin : 2/6/2007<br>wwang : 9/21/2006<br>wwang : 9/7/2006<br>ckniffin : 9/1/2006<br>wwang : 8/29/2006<br>ckniffin : 8/23/2006<br>wwang : 4/12/2006<br>ckniffin : 4/6/2006<br>wwang : 11/14/2005<br>wwang : 10/6/2005<br>ckniffin : 9/26/2005<br>mgross : 5/16/2005<br>terry : 5/12/2005<br>ckniffin : 4/11/2005<br>wwang : 3/8/2005<br>ckniffin : 3/1/2005<br>terry : 8/17/2004<br>tkritzer : 1/27/2004<br>ckniffin : 1/21/2004<br>carol : 2/25/2003<br>ckniffin : 2/19/2003<br>carol : 8/22/2002<br>ckniffin : 8/19/2002<br>ckniffin : 8/19/2002<br>alopez : 11/2/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606439
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<h3>
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<span class="mim-font">
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ATLASTIN GTPase 1; ATL1
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ATLASTIN<br />
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SPG3A GENE; SPG3A
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATL1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 782670003;
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<strong>
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<em>
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Cytogenetic location: 14q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:50,533,082-50,633,068 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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14q22.1
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<span class="mim-font">
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Neuropathy, hereditary sensory, type ID
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<td>
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<span class="mim-font">
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613708
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Spastic paraplegia 3A, autosomal dominant
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<span class="mim-font">
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182600
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ATL1 gene encodes atlastin-1, a dynamin-related GTPase, which plays a role in formation of the tubular endoplasmic reticulum (ER) network and in axon elongation in neurons (Zhu et al., 2006; Orso et al., 2009). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>By positional cloning, Zhao et al. (2001) demonstrated that a form of autosomal dominant hereditary spastic paraplegia with early onset (SPG3A; 182600), before the age of 10 years and usually before the age of 5, is caused by mutation in a GTPase gene. The gene was found to have no homology to genes that cause other forms of hereditary spastic paraplegia. It does show significant homology to guanylate binding protein-1 (GBP1; 600411), a member of the dynamin family of large GTPases. Northern blot analysis of ATL1 expression detected a 2.2-kb transcript primarily in adult and fetal brain. RT-PCR experiments indicated measurable expression in all tissues examined, although expression in adult brain was at least 50-fold higher than in other tissues. Translation of the 2.2-kb cDNA sequence of ATL1 yielded a peptide of 558 amino acids. </p><p>By PCR of a cerebral cortex cDNA library, Zhu et al. (2003) cloned ATL1, which they called atlastin-1. The deduced 558-amino acid protein contains GTP-binding motifs in its N-terminal half and 2 transmembrane domains in its C-terminal half. It also has 3 potential N-glycosylation sites. Western blot analysis of transfected COS-7 cells detected atlastin-1 at an apparent molecular mass of about 64 kD. Western blot analysis detected high atlastin-1 expression in human and rat brain homogenates, with much lower expression in several other human tissues, including smooth muscle, adrenal gland, kidney, testis, and lung. Immunohistochemical analysis of rat brain sections detected high expression of atlastin-1 in cortical neurons of lamina V, pyramidal neurons in CA1 and CA3 of the hippocampus, and in amygdala and several thalamic nuclei. Staining was most prominent in the cell soma, with weaker staining of axons and dendrites. Immunogold labeling detected rat atlastin-1 predominantly in the cis-Golgi cisternae. Protease protection assays indicated that the N and C termini of human atlastin-1 were exposed to the cytoplasmic face of the membrane in transfected cells. </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>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a yeast 2-hybrid assay, Zhu et al. (2003) determined that atlastin-1 self-associates. Chemical cross-linking experiments indicated that atlastin-1 most likely forms a homotetramer of about 230 kD. Zhu et al. (2003) demonstrated that atlastin-1 has GTPase activity. </p><p>Independently, Evans et al. (2006) and Sanderson et al. (2006) demonstrated that the N-terminal domain of spastin (SPAST; 604277) bound directly to the C-terminal cytoplasmic domain of atlastin, suggesting that the 2 gene products interact in a common biologic pathway. Evans et al. (2006) used yeast 2-hybrid analysis and coimmunoprecipitation studies in HeLa cells, and Sanderson et al. (2006) used yeast 2-hybrid analysis of a human fetal brain cDNA library and protein pull-down, coimmunoprecipitation, and colocalization studies in HeLa cells, HEK293T cells, and mouse NSC34 neuronal cells. </p><p>In the developing rat brain, Zhu et al. (2006) found that atlastin-1 was expressed not only in the Golgi apparatus and endoplasmic reticulum, but was also enriched in axonal growth cones and growth cone-like varicosities along the axons. Atlastin-1 labeling was prominent on vesicular structures within the growth cones, but not at the plasma membrane and not at synapses. Knockdown of atlastin-1 using shRNA in cultured cortical cells inhibited axonal growth. Overall, the findings suggested that atlastin-1 has diverse functions in neurons, likely acting both in intracellular membrane trafficking as well as in expansion at the axonal growth cone. These functional studies suggested that the early-onset axonopathy observed in SPG3A may result from abnormal development of axons. </p><p>Orso et al. (2009) demonstrated that Drosophila atlastin localizes on endoplasmic reticulum (ER) membranes and that its loss causes ER fragmentation. Drosophila atlastin embedded in distinct membranes has the ability to form trans-oligomeric complexes, and its overexpression induces enlargement of ER profiles, consistent with excessive fusion of ER membranes. In vitro experiments confirmed that atlastin autonomously drives membrane fusion in a GTP-dependent fashion. In contrast, GTPase-deficient atlastin is inactive, unable to form trans-oligomeric complexes owing to failure to self-associate, and incapable of promoting fusion in vitro. The results of Orso et al. (2009) demonstrated that atlastin mediates membrane tethering and fusion and strongly suggested that it is the GTPase activity required for ER homotypic fusion. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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>Zhao et al. (2001) found that the ATL1 gene contains 14 exons and spans approximately 69 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zhao et al. (2001) determined that the ATL1 gene maps to chromosome 14q11-q21. Zhu et al. (2003) stated that the ATL1 gene maps to chromosome 14q22.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Spastic Paraplegia 3A</em></strong></p><p>
|
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Zhao et al. (2001) identified mutations in the ATL1 gene (see, e.g., 606439.0001) in families with spastic paraplegia-3A (SPG3A; 182600) in which linkage to 14q11-q21 had been demonstrated as well as in other phenotypically similar families without linkage evidence. </p><p>Durr et al. (2004) identified mutations in the ATL1 gene in 12 (39%) of 31 families with early-onset autosomal dominant spastic paraplegia. One family showed incomplete penetrance. </p><p>Namekawa et al. (2006) stated that 19 mutations in the ATL1 gene had been identified in 40 different families. More than 90% of the mutations were located in exons 4 (12.5%), 7 (27.5%), 8 (17.5%), and 12 (35%). </p><p>In COS-7 cells, Zhu et al. (2006) showed that disease-associated missense mutations in the ATL1 gene were expressed and interacted strongly with wildtype ATL1, causing a decrease in GTPase activity in a dominant-negative manner. The GTPase impairment was strongest with the R217Q mutation (606439.0004), which is located within the GTPase binding site, but was also observed with other missense mutations (R239C; 606439.0001 and H258R; 606439.0003), suggesting that these regions may modulate activity. </p><p>Beetz et al. (2007) reported a family in which spastic paraplegia segregated with a deletion of exon 1 of the SPAST gene (604277) in the proband, her brother, and her 2 sons. Although the proband and her brother also had a deletion of the ATL1 gene, the ATL1 deletion did not segregate with the disorder in her sons and had no apparent effect on the severity of the disorder. The findings suggested that haploinsufficiency is the pathogenic mechanism for SPG4 (182601), whereas a dominant-negative effect is the pathogenic mechanism for SPG3A. </p><p><strong><em>Hereditary Sensory Neuropathy Type 1D</em></strong></p><p>
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By genomewide linkage analysis followed by array-based exonic sequencing of candidate genes, Guelly et al. (2011) identified a heterozygous mutation in the ATL1 gene (N355K; 606439.0010) as a cause of autosomal dominant hereditary neuropathy type 1D (HSN1D; 613708) in an affected family. Screening of this gene in 115 additional probands with a similar disorder identified 2 additional heterozygous mutations in the ATL1 gene in 2 unrelated probands (606439.0011 and 606439.0012, respectively). The phenotype was characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients showed features suggesting upper neuron involvement. In vitro functional expression studies in COS-7 cells did not reveal a common pathogenetic mechanism, and there was no clear functional distinction between mutations causing SPG3A and HSN1D, but Guelly et al. (2011) postulated that a defect in the tubular endoplasmic reticulum may underlie both disorders. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 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 3, 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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ATL1, ARG239CYS
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<br />
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SNP: rs119476046,
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ClinVar: RCV000004594, RCV000215830, RCV000850530, RCV001003978, RCV001847579
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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 apparently unrelated kindreds with spastic paraplegia-3 (182600), Zhao et al. (2001) identified a heterozygous 884C-T transition in exon 7 of the ATL1 gene, resulting in an arg239-to-cys (R239C) substitution. </p><p>Abel et al. (2004) identified the R239C mutation in all 22 affected members of a French family with SPG3 reported by Hazan et al. (1993). Abel et al. (2004) stated that this was the seventh SPG3 family of western European descent found to have the R239C mutation. Abel et al. (2004) reported the nucleotide change as 715C-T, based on numbering from the translation initiation codon, and noted that position 715 is within a CpG doublet, suggesting that it is a possible mutation hotspot. </p><p>By haplotype analysis of 3 French families with the R239C mutation, Namekawa et al. (2006) concluded that the mutations arose independently and were not due to a founder effect. Further analysis confirmed that the mutation occurred in a hotspot defined by a methylated CpG dinucleotide. </p>
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</span>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPASTIC PARAPLEGIA 3, 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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ATL1, SER259TYR
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<br />
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SNP: rs119476047,
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ClinVar: RCV000004595
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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 kindred designated ADHSP-P with early-onset autosomal dominant spastic paraplegia (182600), Zhao et al. (2001) identified heterozygosity (both C and A) at nucleotide 945 of the full-length ATL1 cDNA, corresponding to exon 8 of the gene. Unaffected members of the family had only C at this position. This mutation, TCC (ser) to TAC (tyr), was predicted to alter amino acid 259. Thus, this mutation, S259Y, is adjacent to the H258R mutation (606439.0003). </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 SPASTIC PARAPLEGIA 3, 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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ATL1, HIS258ARG
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<br />
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SNP: rs119476048,
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ClinVar: RCV000004596
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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>Zhao et al. (2001) found that affected members in a kindred with autosomal dominant hereditary spastic paraplegia of early onset (182600) were heterozygous (A and G) at nucleotide position 942 of the full-length cDNA corresponding to the ATL1 gene. Affected members in this kindred had only C at this position. The mutation was predicted to result in a his258-to-arg (H258R) amino acid substitution, at a site adjacent to S259Y (606439.0002). </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 SPASTIC PARAPLEGIA 3, 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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ATL1, ARG217GLN
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<br />
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SNP: rs119476049,
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ClinVar: RCV000004597, RCV001725929
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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 large Italian family with early-onset, autosomal dominant uncomplicated spastic paraplegia (182600), Muglia et al. (2002) identified an 818G-A mutation in the ATL1 gene, resulting in an arg217-to-gln substitution in a highly conserved GTPase motif. </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>.0005 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</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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ATL1, 1-BP INS, 1688A
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<br />
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SNP: rs863223314,
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ClinVar: RCV000020718
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In an Italian family with autosomal dominant hereditary spastic paraplegia (182600), Tessa et al. (2002) identified a heterozygous 1-bp insertion, 1688A, in exon 12 of the ATL1 gene, producing a frameshift and premature stop codon. The resulting protein lacked the last 37 amino acids, including all of exon 14. Seven clearly affected individuals and 2 asymptomatic individuals with hyperreflexia carried the mutation. The authors commented on the apparent age-dependent penetrance of the disorder in this family. </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>
|
|
<span class="mim-font">
|
|
<strong>.0006 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</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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ATL1, MET408VAL
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<br />
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SNP: rs28939094,
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|
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ClinVar: RCV000004599
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a family with 6 members affected with a very early onset severe form of spastic paraplegia (182600), Dalpozzo et al. (2003) identified a heterozygous 1222A-G transition in exon 12 of the ATL1 gene, resulting in a met408-to-val (M408V) substitution. All affected members had onset in infancy with delayed motor milestones, gait impairment, spastic paraparesis, distal atrophy, and lower limb weakness. Because of the very early onset, the first patients were misdiagnosed with cerebral palsy, and the index patient (mother of 5 affected members) was unaware that she had a genetically transmissible disease. Two patients had the unusual sign of mild hand atrophy. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</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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|
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ATL1, ARG415TRP
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<br />
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|
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SNP: rs119476050,
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|
|
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gnomAD: rs119476050,
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|
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ClinVar: RCV000004600, RCV000190652, RCV001090532
|
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|
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</span>
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|
</div>
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|
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<div>
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|
<span class="mim-text-font">
|
|
<p>In all 3 affected members tested from an Italian family with SPG3A (182600), D'Amico et al. (2004) identified a heterozygous mutation in exon 12 of the atlastin gene, resulting in an arg415-to-trp (R415W) substitution. The mutation was not identified in 400 control chromosomes. The 3 patients had onset before 5 years of age, and 2 additional family members were reportedly affected by infantile-onset spastic paraparesis. However, 9 asymptomatic relatives ranging in age from 13 to 70 years also had the mutation. D'Amico et al. (2004) concluded that the reduced penetrance of this mutation indicated that modulator genes or epigenetic factors are involved in the development of the disease, and they noted the implications for genetic counseling. </p><p>Varga et al. (2013) identified a heterozygous c.1243C-T transition in the ATL1 gene resulting in an R415W substitution in affected members of a family with SPG3A originally reported by Raggio et al. (1973) as having a pure spastic paraplegia transmitted in an X-linked pattern of inheritance. Whole-exome sequencing of 1 of the affected males identified the heterozygous R415W substitution. This mutation was then identified in 3 affected family members and in 3 unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. Varga et al. (2013) identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families. Varga et al. (2013) also identified a heterozygous c.1244A-G transition, resulting in an arg415-to-gln (R415Q; 606439.0014) substitution, in a Moroccan family with SPG3A and incomplete penetrance. Varga et al. (2013) noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 affects a highly conserved residue that does not localize to a known protein domain. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, LEU157TRP
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs119476051,
|
|
|
|
|
|
|
|
ClinVar: RCV000004601
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with SPG3A (182600), Rainier et al. (2006) identified a heterozygous 638T-C transition in exon 4 of the ATL1 gene, resulting in a leu157-to-trp (L157W) substitution. The mutation is predicted to disrupt a putative phosphorylation site of the protein. Genetic analysis of family members indicated that the mutation occurred de novo in the mother. The mother was a 34-year-old woman with uncomplicated nonprogressive spastic paraplegia since infancy who was originally diagnosed with spastic diplegic cerebral palsy. She was correctly diagnosed with SPG after her son developed similar clinical symptoms at age 10 months. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, 3-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1595625206,
|
|
|
|
|
|
|
|
ClinVar: RCV000004602, RCV001847580
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large French Canadian family with SPG3A (182600), Meijer et al. (2007) identified a heterozygous 3-bp in-frame deletion in the ATL1 gene, resulting in a deletion of asn436 (436delN). Functional expression studies showed decreased ATL1 protein levels in patients' lymphoblasts but normal levels of mRNA, normal GTPase activity, and normal protein interactions. Meijer et al. (2007) postulated decreased protein stability and a dominant-negative loss-of-function mechanism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NEUROPATHY, HEREDITARY SENSORY, TYPE ID</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, ASN355LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555365597,
|
|
|
|
|
|
|
|
ClinVar: RCV000023542, RCV000626932, RCV000789726
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large 4-generation family with autosomal dominant hereditary sensory neuropathy type ID (HSN1D; 613708), Guelly et al. (2011) identified a heterozygous 1065C-A transversion in exon 11 of the ATL1 gene, resulting in an asn355-to-lys (N355K) substitution. The mutation was not found in 370 controls. The phenotype was characterized by early adult onset of a severe distal st sensory axonal neuropathy with frequent ulcerations and amputation digits. In vitro functional expression studies in COS-7 cells showed that the mutant protein had decreased GTPase activity compared to wildtype, and caused disruption of endoplasmic reticulum 3-way junctions. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEUROPATHY, HEREDITARY SENSORY, TYPE ID</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, GLU66GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200314808,
|
|
|
|
|
|
gnomAD: rs200314808,
|
|
|
|
|
|
ClinVar: RCV000023543, RCV000236565, RCV000543629, RCV002415427
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 61-year-old man with hereditary sensory neuropathy-1D (HSN1D; 613708), Guelly et al. (2011) identified a heterozygous 196G-C transversion in exon 2 of the ATL1 gene, resulting in a glu66-to-gln (E66Q) substitution. He presented with progressive, ascending, severe sensory loss affecting all modalities in the lower legs, but no foot ulcerations or paresis. He had hyporeflexia, and sural nerve biopsy revealed a severe, chronic, axonal neuropathy with a moderate demyelinating component. The patient's deceased mother reportedly had a similar severe sensory neuropathy. The mutation was not found in 150 control individuals, but in vitro functional expression studies showed no change in GTPase activity and no changes in endoplasmic reticulum morphology. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NEUROPATHY, HEREDITARY SENSORY, TYPE ID</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, 1-BP DEL, 976G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1595619553,
|
|
|
|
|
|
|
|
ClinVar: RCV000023544, RCV000789725
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with hereditary sensory neuropathy-1D (HSN1D; 613708), Guelly et al. (2011) identified a heterozygous 1-bp deletion (976delG) in exon 9 of the ATL1 gene, resulting in premature termination in the C terminus. The patient had adult-onset sensory neuropathy with ulcerations, lack of pain perception, paresthesias in the fingers, and occasional lancinating pains in his ankles. Patellar tendon reflexes were brisk, and Achilles tendon reflexes were absent. His father and brother were similarly affected. The mutation was not found in 334 control individuals. In vitro functional expression studies showed decreased expression of the truncated protein and diffuse localization throughout the cytoplasm instead of proper localization to the endoplasmic reticulum. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, ARG416CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906941,
|
|
|
|
|
|
gnomAD: rs387906941,
|
|
|
|
|
|
ClinVar: RCV000023545, RCV001847621, RCV002285257, RCV002513195, RCV004767019
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation South African Zulu family with autosomal dominant SPG3A (182600), Orlacchio et al. (2011) identified a heterozygous 1246C-T transition in exon 12 of the ATL1 gene, resulting in an arg416-to-cys (R416C) substitution. The mutation was not found in 400 controls. The phenotype in this family was unusual in that affected individuals had late onset (range 38 to 56 years), mild mental retardation (IQ 32 to 67), and thin corpus callosum without cerebellar involvement or white matter abnormalities. Spasticity was restricted to the lower limbs; 3 patients had sphincter disturbances. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATL1, ARG415GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514712,
|
|
|
|
|
|
gnomAD: rs397514712,
|
|
|
|
|
|
ClinVar: RCV000050231, RCV000480817
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 Moroccan sibs with SPG3A (182600), Varga et al. (2013) identified a c.1244A-G transition in the ATL1 gene, resulting in an arg415-to-gln (R415Q) substitution. Three sibs were homozygous and 1 was heterozygous for the mutation. Heterozygosity for the mutation was then found in 3 unaffected family members and in 2 family members who had very subtle signs of the disorder (hyperreflexia). These findings suggested complete penetrance for the mutation in homozygous state and incomplete penetrance for the mutation in heterozygous state. Varga et al. (2013) also identified a heterozygous c.1243C-T transition, resulting in an R415W (606439.0007) substitution in another family with SPG3A and incomplete penetrance. Varga et al. (2013) noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 is a highly conserved residue that does not localize to a known protein domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<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>.0015 VARIANT OF UNKNOWN SIGNIFICANCE</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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ATL1, ARG118GLN
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<br />
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SNP: rs606231265,
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gnomAD: rs606231265,
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ClinVar: RCV000144894, RCV000281684, RCV002514782
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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>This variant is classified as a variant of unknown significance because its contribution to an autosomal recessive form of SPG3A (see 182600) has not been confirmed.</p><p>In 6 males from a large Pakistani family with SPG3A, Khan et al. (2014) identified a homozygous c.353G-A transition in exon 4 of the ATL1 gene, resulting in an arg118-to-gln (R118Q) substitution at a highly conserved residue in the GTPase domain. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Variant Server database or in 200 Pakistani control chromosomes. Functional studies of the variant were not performed. The affected males who were homozygous for the variant presented with pure SPG before 2 years of age. Seven family members were heterozygous for the variant, all of whom were asymptomatic except for 1 woman who had subclinically reduced vibration sensation. Khan et al. (2014) concluded that SPG3A in this family was transmitted in an autosomal recessive pattern, adding to the clinical complexity of the disorder. </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>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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Abel, A., Fonknechten, N., Hofer, A., Durr, A., Cruaud, C., Voit, T., Weissenbach, J., Brice, A., Klimpe, S., Auburger, G., Hazan, J.
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<strong>Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A.</strong>
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Neurogenetics 5: 239-243, 2004.
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[PubMed: 15517445]
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[Full Text: https://doi.org/10.1007/s10048-004-0191-2]
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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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Beetz, C., Nygren, A. O. H., Deufel, T., Reid, E.
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<strong>An SPG3A whole gene deletion neither co-segregates with disease nor modifies phenotype in a hereditary spastic paraplegia family with a pathogenic SPG4 mutation. (Letter)</strong>
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Neurogenetics 8: 317-318, 2007.
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[PubMed: 17657515]
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[Full Text: https://doi.org/10.1007/s10048-007-0099-8]
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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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D'Amico, A., Tessa, A., Sabino, A., Bertini, E., Santorelli, F. M., Servidei, S.
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<strong>Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.</strong>
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Neurology 62: 2138-2139, 2004.
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[PubMed: 15184642]
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[Full Text: https://doi.org/10.1212/01.wnl.0000127698.88895.85]
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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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Dalpozzo, F., Rossetto, M. G., Boaretto, F., Sartori, E., Mostacciuolo, M. L., Daga, A., Bassi, M. T., Martinuzzi, A.
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<strong>Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation.</strong>
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Neurology 61: 580-581, 2003. Note: Erratum: Neurology 62: 348 only, 2004.
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[PubMed: 12939451]
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[Full Text: https://doi.org/10.1212/01.wnl.0000078189.73611.df]
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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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Durr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Rossi, A., Gil, R., Rousselle, C., Ruberg, M., Stevanin, G., Brice, A.
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<strong>Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.</strong>
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Arch. Neurol. 61: 1867-1872, 2004.
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[PubMed: 15596607]
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[Full Text: https://doi.org/10.1001/archneur.61.12.1867]
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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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Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B., Lauring, B.
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<strong>Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance.</strong>
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Proc. Nat. Acad. Sci. 103: 10666-10671, 2006.
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[PubMed: 16815977]
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[Full Text: https://doi.org/10.1073/pnas.0510863103]
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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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Guelly, C., Zhu, P.-P., Leonardis, L., Papic, L., Zidar, J., Schabhuttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Frohlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., Auer-Grumbach, M.
|
|
<strong>Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.</strong>
|
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Am. J. Hum. Genet. 88: 99-105, 2011.
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[PubMed: 21194679]
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[Full Text: https://doi.org/10.1016/j.ajhg.2010.12.003]
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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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Hazan, J., Lamy, C., Melki, J., Munnich, A., de Recondo, J., Weissenbach, J.
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<strong>Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q.</strong>
|
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Nature Genet. 5: 163-167, 1993.
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[PubMed: 8252041]
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[Full Text: https://doi.org/10.1038/ng1093-163]
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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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Khan, T. N., Klar, J., Tariq, M., Anjum Baig, S., Malik, N. A., Yousaf, R., Baig, S. M., Dahl, N.
|
|
<strong>Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.</strong>
|
|
Europ. J. Hum. Genet. 22: 1180-1184, 2014.
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[PubMed: 24473461]
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[Full Text: https://doi.org/10.1038/ejhg.2014.5]
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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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Meijer, I. A., Dion, P., Laurent, S., Dupre, N., Brais, B., Levert, A., Puymirat, J., Rioux, M. F., Sylvain, M., Zhu, P.-P., Soderblom, C., Stadler, J., Blackstone, C., Rouleau, G. A.
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<strong>Characterization of a novel SPG3A deletion in a French-Canadian family.</strong>
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Ann. Neurol. 61: 599-603, 2007.
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[PubMed: 17427918]
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[Full Text: https://doi.org/10.1002/ana.21114]
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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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Muglia, M., Magariello, A., Nicoletti, G., Patitucci, A., Gabriele, A. L., Conforti, F. L., Mazzei, R., Caracciolo, M., Ardito, B., Lastilla, M., Tedeschi, G., Quattrone, A.
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<strong>Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia.</strong>
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|
Ann. Neurol. 51: 794-795, 2002.
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[PubMed: 12112092]
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[Full Text: https://doi.org/10.1002/ana.10185]
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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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Namekawa, M., Nelson, I., Ribai, P., Durr, A., Denis, E., Stevanin, G., Ruberg, M., Brice, A.
|
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<strong>A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. (Letter)</strong>
|
|
Neurogenetics 7: 131-132, 2006.
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[PubMed: 16612642]
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[Full Text: https://doi.org/10.1007/s10048-006-0028-2]
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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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Namekawa, M., Ribai, P., Nelson, I., Forlani, S., Fellmann, F., Goizet, C., Depienne, C., Stevanin, G., Ruberg, M., Durr, A., Brice, A.
|
|
<strong>SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.</strong>
|
|
Neurology 66: 112-114, 2006.
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[PubMed: 16401858]
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[Full Text: https://doi.org/10.1212/01.wnl.0000191390.20564.8e]
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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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Orlacchio, A., Montieri, P., Babalini, C., Gaudiello, F., Bernardi, G., Kawarai, T.
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<strong>Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation. (Letter)</strong>
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J. Neurol. 258: 1361-1363, 2011.
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[PubMed: 21336785]
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[Full Text: https://doi.org/10.1007/s00415-011-5934-z]
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</p>
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<li>
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<p class="mim-text-font">
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Orso, G., Pendin, D., Liu, S., Tosetto, J., Moss, T. J., Faust, J. E., Micaroni, M., Egorova, A., Martinuzzi, A., McNew, J. A., Daga, A.
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<strong>Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin.</strong>
|
|
Nature 460: 978-983, 2009. Note: Erratum: Nature 464: 942 only, 2010.
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[PubMed: 19633650]
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[Full Text: https://doi.org/10.1038/nature08280]
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</p>
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<p class="mim-text-font">
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Raggio, J. F., Thurmon, T. F., Anderson, E. E.
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<strong>X-linked hereditary spastic paraplegia.</strong>
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J. La. State Med. Soc. 125: 4-6, 1973.
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[PubMed: 4684346]
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<li>
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<p class="mim-text-font">
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Rainier, S., Sher, C., Reish, O., Thomas, D., Fink, J. K.
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<strong>De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.</strong>
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Arch. Neurol. 63: 445-447, 2006.
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[PubMed: 16533974]
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[Full Text: https://doi.org/10.1001/archneur.63.3.445]
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</p>
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<li>
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<p class="mim-text-font">
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Sanderson, C. M., Connell, J. W., Edwards, T. L., Bright, N. A., Duley, S., Thompson, A., Luzio, J. P., Reid, E.
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<strong>Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners.</strong>
|
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Hum. Molec. Genet. 15: 307-318, 2006.
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[PubMed: 16339213]
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[Full Text: https://doi.org/10.1093/hmg/ddi447]
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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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Tessa, A., Casali, C., Damiano, M., Bruno, C., Fortini, D., Patrono, C., Cricchi, F., Valoppi, M., Nappi, G., Amabile, G. A., Bertini, E., Santorelli, F. M.
|
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<strong>SPG3A: an additional family carrying a new atlastin mutation.</strong>
|
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Neurology 59: 2002-2005, 2002.
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[PubMed: 12499504]
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[Full Text: https://doi.org/10.1212/01.wnl.0000036902.21438.98]
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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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Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C.
|
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<strong>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.</strong>
|
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Hum. Mutat. 34: 860-863, 2013.
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[PubMed: 23483706]
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[Full Text: https://doi.org/10.1002/humu.22309]
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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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Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J. K.
|
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<strong>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.</strong>
|
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Nature Genet. 29: 326-331, 2001.
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[PubMed: 11685207]
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[Full Text: https://doi.org/10.1038/ng758]
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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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Zhu, P.-P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C.
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<strong>Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin.</strong>
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J. Biol. Chem. 278: 49063-49071, 2003.
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[PubMed: 14506257]
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[Full Text: https://doi.org/10.1074/jbc.M306702200]
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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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Zhu, P.-P., Soderblom, C., Tao-Cheng, J.-H., Stadler, J., Blackstone, C.
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<strong>SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.</strong>
|
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Hum. Molec. Genet. 15: 1343-1353, 2006.
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[PubMed: 16537571]
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[Full Text: https://doi.org/10.1093/hmg/ddl054]
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</li>
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</ol>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Cassandra L. Kniffin - updated : 11/3/2014<br>Cassandra L. Kniffin - updated : 7/25/2013<br>Cassandra L. Kniffin - updated : 10/11/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Cassandra L. Kniffin - updated : 10/15/2010<br>Patricia A. Hartz - updated : 11/11/2009<br>Ada Hamosh - updated : 9/15/2009<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 11/27/2007<br>Cassandra L. Kniffin - updated : 2/6/2007<br>Cassandra L. Kniffin - updated : 9/1/2006<br>Cassandra L. Kniffin - updated : 8/23/2006<br>Cassandra L. Kniffin - updated : 4/6/2006<br>Cassandra L. Kniffin -updated : 9/26/2005<br>Patricia A. Hartz - updated : 5/12/2005<br>Cassandra L. Kniffin - updated : 4/11/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Cassandra L. Kniffin - updated : 2/19/2003<br>Cassandra L. Kniffin - updated : 8/19/2002
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</span>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/2/2001
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<span class="text-nowrap mim-text-font">
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Edit History:
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carol : 11/06/2014<br>mcolton : 11/3/2014<br>ckniffin : 11/3/2014<br>carol : 12/16/2013<br>carol : 9/16/2013<br>carol : 7/26/2013<br>ckniffin : 7/25/2013<br>carol : 10/13/2011<br>carol : 10/13/2011<br>carol : 10/13/2011<br>terry : 10/12/2011<br>ckniffin : 10/11/2011<br>wwang : 3/2/2011<br>wwang : 2/23/2011<br>wwang : 2/23/2011<br>ckniffin : 1/28/2011<br>wwang : 10/27/2010<br>ckniffin : 10/15/2010<br>alopez : 6/1/2010<br>mgross : 11/13/2009<br>terry : 11/11/2009<br>alopez : 9/15/2009<br>terry : 9/15/2009<br>wwang : 1/15/2008<br>ckniffin : 12/27/2007<br>wwang : 12/4/2007<br>ckniffin : 11/27/2007<br>wwang : 2/8/2007<br>ckniffin : 2/6/2007<br>wwang : 9/21/2006<br>wwang : 9/7/2006<br>ckniffin : 9/1/2006<br>wwang : 8/29/2006<br>ckniffin : 8/23/2006<br>wwang : 4/12/2006<br>ckniffin : 4/6/2006<br>wwang : 11/14/2005<br>wwang : 10/6/2005<br>ckniffin : 9/26/2005<br>mgross : 5/16/2005<br>terry : 5/12/2005<br>ckniffin : 4/11/2005<br>wwang : 3/8/2005<br>ckniffin : 3/1/2005<br>terry : 8/17/2004<br>tkritzer : 1/27/2004<br>ckniffin : 1/21/2004<br>carol : 2/25/2003<br>ckniffin : 2/19/2003<br>carol : 8/22/2002<br>ckniffin : 8/19/2002<br>ckniffin : 8/19/2002<br>alopez : 11/2/2001
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