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Entry
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- *606352 - ALSIN RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR ALS2; ALS2
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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">*606352</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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606352">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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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000003393;t=ENST00000264276" 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=57679" 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=606352" 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="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<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=ENSG00000003393;t=ENST00000264276" 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_001135745,NM_001410975,NM_020919,XM_006712654,XM_006712655,XM_017004570,XM_017004572,XM_047445224,XM_047445238,XM_047445241" 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_020919" 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=606352" 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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</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=05893&isoform_id=05893_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/ALS2" 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/10434747,15823636,15823638,16076812,20810130,40316935,47938104,62702255,62822510,119590697,119590698,119590699,158255494,193786419,209364523,296434394,578804652,578804654,929654869,957951423,957951427,1034615477,1034615485,1403730222,2217329888,2217329891,2217329893,2287780807,2462575658,2462575660,2462575662,2462575664,2462575666,2462575668,2462575670,2462575672,2462575674,2462575676,2462575678,2462575680" 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/Q96Q42" 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 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=57679" 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=ENSG00000003393;t=ENST00000264276" 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=ALS2" 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=ALS2" 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+57679" 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/ALS2" 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:57679" 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/57679" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr2&hgg_gene=ENST00000264276.11&hgg_start=201700267&hgg_end=201780933&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/gene-dosage/HGNC:443" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:443" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/als2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606352[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=606352[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/ALS2/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/ENSG00000003393" 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=ALS2" 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=ALS2" 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=ALS2" 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=ALS2&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/PA24732" 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:443" 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/FBgn0037116.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:1921268" 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/ALS2#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:1921268" 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/57679/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=57679" 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://zfin.org/ZDB-GENE-070402-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:57679" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=ALS2&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> 703543005, 717964007<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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606352
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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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ALSIN RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR ALS2; ALS2
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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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ALSIN<br />
|
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ALS2 GENE<br />
|
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KIAA1563
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ALS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ALS2</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/2/921?start=-3&limit=10&highlight=921">2q33.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:201700267-201780933&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">2:201,700,267-201,780,933</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>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=205100,606353,607225" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/921?start=-3&limit=10&highlight=921">
|
|
2q33.1
|
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</a>
|
|
</span>
|
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</td>
|
|
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 2, juvenile
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/205100"> 205100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</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>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Primary lateral sclerosis, juvenile
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/606353"> 606353 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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<p>Alsin, which is encoded by the ALS2 gene, is a member of the guanine nucleotide exchange factors for the small GTPase RAB5 (<a href="/entry/179512">179512</a>) and plays a role in intracellular endosomal trafficking (summary by <a href="#8" class="mim-tip-reference" title="Hadano, S., Benn, S. C., Kakuta, S., Otomo, A., Sudo, K., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Shefner, J. M., Cox, G. A., Iwakura, Y., Brown, R. H., Jr., Ikeda, J.-E. <strong>Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking.</strong> Hum. Molec. Genet. 15: 233-250, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321985</a>] [<a href="https://doi.org/10.1093/hmg/ddi440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321985">Hadano et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321985" 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="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> and <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> isolated a gene found to be mutant in families with juvenile amyotrophic lateral sclerosis-2 (ALS2; <a href="/entry/205100">205100</a>) or juvenile primary lateral sclerosis (PLSJ; <a href="/entry/606353">606353</a>). The coding sequence gives rise to a deduced 184-kD 1,657-residue long form of the protein, and alternative splicing after exon 4 yields a 396-residue short form. <a href="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> and <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> both determined that the deduced ALS2 protein contains several guanine-nucleotide exchange factor domains, consistent with a function in cell signaling. By Northern blot analysis, <a href="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> detected 2 mRNA bands of 2.3 and 6 kb, whereas <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> reported mRNA bands of 2.6 and 6.5 kb. The ALS2 gene is expressed in various tissues and cells, including neurons throughout the brain and spinal cord. It was found to be identical to KIAA1563, identified by <a href="#19" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11586298+10997877+11586297" 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="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> and <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> independently determined that the ALS2 gene comprises 34 exons in a genomic region of 83 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11586298+11586297" 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="#20" class="mim-tip-reference" title="Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., Showguchi-Miyata, J., Yanagisawa, Y., Kohiki, E., Suga, E., Yasuda, M., Osuga, H., Nishimoto, T., Narumiya, S., Ikeda, J.-E. <strong>ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.</strong> Hum. Molec. Genet. 12: 1671-1687, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12837691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12837691</a>] [<a href="https://doi.org/10.1093/hmg/ddg184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12837691">Otomo et al. (2003)</a> showed that the ALS2 protein specifically binds to small GTPase RAB5 (<a href="/entry/179512">179512</a>) and functions as a guanine nucleotide exchange factor (GEF) for RAB5. Ectopically expressed ALS2 localized with RAB5 and early endosome antigen-1 (EEA1; <a href="/entry/605070">605070</a>) onto early endosomal compartments and stimulated the enlargement of endosomes in cultured cortical neurons. The C terminus of ALS2 carrying a VPS9 domain mediated not only the activation of RAB5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of ALS2, whereas the N-terminal region containing the RCC1 (<a href="/entry/179710">179710</a>)-like domain acted suppressive in its membranous localization. The DH/PH domain in the middle portion of ALS2 enhanced the VPS9 domain-mediated endosome fusions. <a href="#20" class="mim-tip-reference" title="Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., Showguchi-Miyata, J., Yanagisawa, Y., Kohiki, E., Suga, E., Yasuda, M., Osuga, H., Nishimoto, T., Narumiya, S., Ikeda, J.-E. <strong>ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.</strong> Hum. Molec. Genet. 12: 1671-1687, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12837691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12837691</a>] [<a href="https://doi.org/10.1093/hmg/ddg184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12837691">Otomo et al. (2003)</a> hypothesized that a perturbation of endosomal dynamics caused by loss of the ALS2 functional domain that confers RAB5 GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12837691" 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="Kanekura, K., Hashimoto, Y., Niikura, T., Aiso, S., Matsuoka, M., Nishimoto, I. <strong>Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants.</strong> J. Biol. Chem. 279: 19247-19256, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14970233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14970233</a>] [<a href="https://doi.org/10.1074/jbc.M313236200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14970233">Kanekura et al. (2004)</a> found that the long 1,657-residue isoform of ALS2 bound to mutant SOD1 (<a href="/entry/147450">147450</a>) via the RhoGEF domain and protected mouse motor neurons from toxicity induced by mutant SOD1. In contrast, the short 396-residue isoform of ALS2 and truncating pathogenic ALS2 mutations did not protect mouse neurons from mutant SOD1 toxicity. The long isoform of ALS2 did not bind to wildtype SOD1, but the short ALS2 isoform did bind to wildtype SOD1. Further studies indicated that the C-terminal region of ALS2 prevents the long isoform from binding to wildtype SOD1. The long isoform of ALS2 did not protect neurons against other non-ALS insults, such as mutant PS1 (<a href="/entry/104311">104311</a>), SNCA (<a href="/entry/163890">163890</a>), or APP (<a href="/entry/104760">104760</a>). The findings suggested a functional link between 2 ALS-related genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14970233" 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>Among 3 families reported by <a href="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> and <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a>, 1 had a 1-bp deletion in exon 3 (<a href="#0001">606352.0001</a>) of the ALS2 gene, which resulted in the more severe juvenile ALS phenotype, whereas 2 had 2-bp deletions in exons 9 and 5 of the ALS2 gene, (<a href="#0002">606352.0002</a>; <a href="#0004">606352.0004</a>), respectively, which resulted in the milder juvenile primary lateral sclerosis phenotype. The authors suggested that the milder PLSJ phenotype may have occurred because of an intact short protein or some preservation of function of the mutated longer protein. The truncating nature of the mutations and the recessive pattern of inheritance suggested that motor neuron degeneration is the result of a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11586298+11586297" 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="Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. <strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong> Am. J. Hum. Genet. 71: 518-527, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145748">Eymard-Pierre et al. (2002)</a> identified homozygous mutations in the ALS2 gene (<a href="#0005">606352.0005</a>-<a href="#0008">606352.0008</a>) in affected members of 4 of 10 families with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>). All the mutations led to a truncated alsin protein. The authors noted that ALS2 mutations are responsible for a primitive, retrograde degeneration of the upper motor neurons of the pyramidal tracts, resulting in a clinical continuum from infantile (IAHSP) to juvenile forms with (ALS2) or without (PLSJ) lower motor neuron involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145748" 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="Al-Chalabi, A., Hansen, V. K., Simpson, C. L., Xi, J., Hosler, B. A., Powell, J. F., McKenna-Yasek, D., Shaw, C. E., Leigh, P. N., Brown, R. H., Jr. <strong>Variants in the ALS2 gene are not associated with sporadic amyotrophic lateral sclerosis. (Letter)</strong> Neurogenetics 4: 221-222, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12768434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12768434</a>] [<a href="https://doi.org/10.1007/s10048-003-0152-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12768434">Al-Chalabi et al. (2003)</a> stated that 7 mutations in the ALS2 gene had been reported in association with various forms of ALS. However, <a href="#1" class="mim-tip-reference" title="Al-Chalabi, A., Hansen, V. K., Simpson, C. L., Xi, J., Hosler, B. A., Powell, J. F., McKenna-Yasek, D., Shaw, C. E., Leigh, P. N., Brown, R. H., Jr. <strong>Variants in the ALS2 gene are not associated with sporadic amyotrophic lateral sclerosis. (Letter)</strong> Neurogenetics 4: 221-222, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12768434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12768434</a>] [<a href="https://doi.org/10.1007/s10048-003-0152-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12768434">Al-Chalabi et al. (2003)</a> found no significant association between variants in the ALS2 gene and sporadic ALS (see <a href="/entry/105400">105400</a>). The authors concluded that variants of the ALS2 gene are not a common cause of a predominantly early-onset, upper motor neuron disease phenotype of sporadic ALS, nor are they associated with a more typical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12768434" 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>Among 201 patients with familial, sporadic, or early-onset ALS, <a href="#11" class="mim-tip-reference" title="Hand, C. K., Devon, R. S., Gros-Louis, F., Rochefort, D., Khoris, J., Meininger, V., Bouchard, J.-P., Camu, W., Hayden, M. R., Rouleau, G. A. <strong>Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis.</strong> Arch. Neurol. 60: 1768-1771, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676054</a>] [<a href="https://doi.org/10.1001/archneur.60.12.1768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676054">Hand et al. (2003)</a> found no pathogenic mutations in the ALS2 gene, suggesting that mutations in the ALS2 gene are not a common cause of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Devon, R. S., Orban, P. C., Gerrow, K., Barbieri, M. A., Schwab, C., Cao, L. P., Helm, J. R., Bissada, N., Cruz-Aguado, R., Davidson, T.-L., Witmer, J., Metzler, M., Lam, C. K., Tetzlaff, W., Simpson, E. M., McCaffery, J. M., El-Husseini, A. E., Leavitt, B. R., Hayden, M. R. <strong>Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.</strong> Proc. Nat. Acad. Sci. 103: 9595-9600, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16769894[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.0510197103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769894">Devon et al. (2006)</a> found that Als2-null mice were born in the expected mendelian ratio and were indistinguishable from their wildtype littermates in size, appearance, and overall behavior. Als2 deficiency did not affect fertility or fecundity. However, Als2-deficient mice exhibited significant but subtle neuropathologic changes. Cytosol from brains of Als2-null mice showed marked diminution of Rab5-dependent endosome fusion activity. Primary neurons from Als2-null mice showed a disturbance in endosomal transport of Igf1 receptor (IGF1R; <a href="/entry/147370">147370</a>) and Bdnf receptor (NTRK2; <a href="/entry/600456">600456</a>), whereas neuronal viability and endocytosis of transferrin (TF; <a href="/entry/190000">190000</a>) and dextran seemed unaltered. There was a significant decrease in the size of cortical motor neurons, and Als2-null mice were mildly hypoactive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16769894" 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="#26" class="mim-tip-reference" title="Yamanaka, K., Miller, T. M., McAlonis-Downes, M., Chun, S. J., Cleveland, D. W. <strong>Progressive spinal axonal degeneration and slowness in ALS2-deficient mice.</strong> Ann. Neurol. 60: 95-104, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16802286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16802286</a>] [<a href="https://doi.org/10.1002/ana.20888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16802286">Yamanaka et al. (2006)</a> found that Als2-null mice showed progressive axonal degeneration in the lateral spinal cord that was also prominent in mutant SOD1 (<a href="/entry/147450">147450</a>) mice, a model for human ALS. Lower motor neurons were preserved in Als2-null mice, a finding that is distinct from classic ALS, which shows both upper and lower motor neuron involvement. Phenotypically, Als2-null mice showed slowed movement without muscle weakness, consistent with upper motor neuron defects that lead to spasticity in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16802286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Hadano, S., Benn, S. C., Kakuta, S., Otomo, A., Sudo, K., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Shefner, J. M., Cox, G. A., Iwakura, Y., Brown, R. H., Jr., Ikeda, J.-E. <strong>Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking.</strong> Hum. Molec. Genet. 15: 233-250, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321985</a>] [<a href="https://doi.org/10.1093/hmg/ddi440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321985">Hadano et al. (2006)</a> found that Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiologic analyses showed an age-dependent, slowly progressive loss of cerebellar Purkinje cells, a disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, and a progressive loss of motor axons, indicating a subclinical dysfunction of the motor system in Als2-null mice. Quantitative EGF-uptake analysis showed significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of intracellular endosome/vesicle trafficking. Overall, however, the mice did not show a profound defect in motor performance, as seen in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321985" 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="#21" class="mim-tip-reference" title="Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Onoe, K., Osuga, H., Hadano, S., Ikeda, J.-E. <strong>ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth.</strong> Biochem. Biophys. Res. Commun. 370: 87-92, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18358238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18358238</a>] [<a href="https://doi.org/10.1016/j.bbrc.2008.01.177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18358238">Otomo et al. (2008)</a> found that hippocampal neurons from Als2-null mice had a delay in axon outgrowth and decreased macropinocytosis. Als2 colocalized with F-actin in vesicles and in membrane ruffles at the edge of growth cones in sprouting neurites. Axon outgrowth was delayed, but did occur, in Als2-null cells, and the survival rate of the cells was not affected. <a href="#21" class="mim-tip-reference" title="Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Onoe, K., Osuga, H., Hadano, S., Ikeda, J.-E. <strong>ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth.</strong> Biochem. Biophys. Res. Commun. 370: 87-92, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18358238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18358238</a>] [<a href="https://doi.org/10.1016/j.bbrc.2008.01.177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18358238">Otomo et al. (2008)</a> suggested that ALS2 may act as a modulator in neuronal differentiation or development through regulation of membrane dynamics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18358238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Jacquier, A., Bellouze, S., Blanchard, S., Bohl, D., Haase, G. <strong>Astrocytic protection of spinal motor neurons but not cortical neurons against loss of Als2/alsin function.</strong> Hum. Molec. Genet. 18: 2127-2139, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19304783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19304783</a>] [<a href="https://doi.org/10.1093/hmg/ddp136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19304783">Jacquier et al. (2009)</a> demonstrated that alsin-depleted murine spinal motor neurons could be rescued from defective survival and axon growth by cocultured astrocytes. The astrocytic rescue was mediated by an unidentified soluble protective factor rather than by cellular contact. Cortical neurons were intrinsically as vulnerable to alsin depletion as spinal motor neurons, but could not be rescued by cocultured astrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19304783" 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>.0001 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</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">rs386134173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134173;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=rs386134173" 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=rs386134173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Tunisian family with juvenile amyotrophic lateral sclerosis-2 (ALS2; <a href="/entry/205100">205100</a>) reported by <a href="#2" class="mim-tip-reference" title="Ben Hamida, M., Hentati, F., Ben Hamida, C. <strong>Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy.</strong> Brain 113: 347-363, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2328408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2328408</a>] [<a href="https://doi.org/10.1093/brain/113.2.347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2328408">Ben Hamida et al. (1990)</a> and Hentati et al. (<a href="#13" class="mim-tip-reference" title="Hentati, A., Bejaoui, K., Pericak-Vance, M. A., Hentati, F., Yen-Hung, W., Figlewicz, D. A., Ben Hamida, C., Ben Hamida, M., Brown, R. H., Jr., Siddique, T. <strong>The gene locus for one form of juvenile amyotrophic lateral sclerosis maps to chromosome 2. (Abstract)</strong> Am. J. Hum. Genet. 51 (suppl.): A33 only, 1992."None>1992</a>, <a href="#12" class="mim-tip-reference" title="Hentati, A., Bejaoui, K., Pericak-Vance, M. A., Hentati, F., Speer, M. C., Hung, W.-Y., Figlewicz, D. A., Haines, J., Rimmler, J., Ben Hamida, C., Ben Hamida, M., Brown, R. H. Jr., Siddique, T. <strong>Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.</strong> Nature Genet. 7: 425-428, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7920663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7920663</a>] [<a href="https://doi.org/10.1038/ng0794-425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7920663">1994</a>), <a href="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> and <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> identified a homozygous 1-bp deletion (138delA) in exon 3 of the ALS2 gene, resulting in a frameshift and a premature stop codon 4 codons after the deletion site. The 1-bp deletion occurred in codon 46 for alanine and the premature stop was at codon 50. The deletion affected both the long and short forms of the protein. The mutation was not identified in 533 control individuals (<a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11586298+7920663+11586297+2328408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Hadano, S. <strong>Personal Communication.</strong> Isehara, Japan 3/11/2002."None>Hadano (2002)</a> pointed out that this mutation, which <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> identified as 261delA, should be referred to as 138delA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586298" 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> rs386134181 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134181;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/rs386134181?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=rs386134181" 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=rs386134181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected members of a consanguineous Saudi Arabian family with juvenile primary lateral sclerosis (PLSJ; <a href="/entry/606353">606353</a>), <a href="#27" class="mim-tip-reference" title="Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. <strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong> Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>] [<a href="https://doi.org/10.1038/ng1001-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586297">Yang et al. (2001)</a> identified a homozygous 2-bp deletion (1867delCT) in exon 9 of the ALS2 gene. This deletion led to a frameshift and premature stop codon 23 codons after the deletion site. A deletion occurred in codon 623 for leucine and the premature stop was created at codon 646. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586297" 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">rs386134176 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134176;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=rs386134176" 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=rs386134176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Kuwaiti family reported by <a href="#17" class="mim-tip-reference" title="Lerman-Sagie, T., Filiano, J., Smith, D. W., Korson, M. <strong>Infantile onset of hereditary ascending spastic paralysis with bulbar involvement.</strong> J. Child. Neurol. 11: 54-57, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8745388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8745388</a>] [<a href="https://doi.org/10.1177/088307389601100114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8745388">Lerman-Sagie et al. (1996)</a> in which affected members showed early development of progressive spasticity but no evidence of denervation in the first 2 decades of life, <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> identified a homozygous 2-bp deletion (1425delAG) in exon 5 of the ALS2 gene. <a href="#22" class="mim-tip-reference" title="Shaw, P. J. <strong>Genetic inroads in familial ALS.</strong> Nature Genet. 29: 103-104, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586285</a>] [<a href="https://doi.org/10.1038/ng1001-103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586285">Shaw (2001)</a> classified this family as having primary lateral sclerosis (PLSJ; <a href="/entry/606353">606353</a>) because of the lack of evidence of denervation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11586298+8745388+11586285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a personal communication, <a href="#10" class="mim-tip-reference" title="Hadano, S. <strong>Personal Communication.</strong> Isehara, Japan 3/11/2002."None>Hadano (2002)</a> pointed out that the mutation identified by <a href="#9" class="mim-tip-reference" title="Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. <strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong> Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>] [<a href="https://doi.org/10.1038/ng1001-166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586298">Hadano et al. (2001)</a> as 1548delAG should be referred to as 1425delAG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 members of a family (family 362) with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#5" class="mim-tip-reference" title="Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. <strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong> Am. J. Hum. Genet. 71: 518-527, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145748">Eymard-Pierre et al. (2002)</a> found a homozygous 1-bp deletion (3742delA) in exon 22 in the long ALS2 transcript, causing a frameshift and a stop codon at met1206. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145748" 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">rs387906316 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906316;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=rs387906316" 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=rs387906316" 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=RCV000004659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004659</a>
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<p>In a patient (family 419) with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#5" class="mim-tip-reference" title="Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. <strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong> Am. J. Hum. Genet. 71: 518-527, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145748">Eymard-Pierre et al. (2002)</a> found a homozygous 10-bp deletion at nucleotide 1471 in exon 6 of the long ALS2 transcript. The deletion led to a frameshift and a premature stop codon at amino acid 493. Genomic DNA analysis with primers amplifying exon 6 and the corresponding splice site regions demonstrated a homozygous point mutation (G to T) in the consensus CAG acceptor splice site of exon 6. Both parents and 1 unaffected sib were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145748" 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>.0007 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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ALS2, 2-BP DEL, 2660AT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134183;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=rs386134183" 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=rs386134183" 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=RCV000004660" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004660" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004660</a>
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<p>In a patient (family 283) with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#5" class="mim-tip-reference" title="Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. <strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong> Am. J. Hum. Genet. 71: 518-527, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145748">Eymard-Pierre et al. (2002)</a> found a homozygous 2-bp deletion at nucleotide 2660 (2660delAT) in exon 13 of the long ALS2 transcript. The deletion led to a frameshift at asn845 and a premature stop codon 12 codons after the deletion site at amino acid 858. The parents for heterozygous for the mutation, and an unaffected brother was homozygous for the normal allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145748" 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="0008" class="mim-anchor"></a>
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<strong>.0008 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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ALS2, 2-BP DEL, 1130AT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134175 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134175;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=rs386134175" 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=rs386134175" 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=RCV000004661" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004661" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004661</a>
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<p>In a patient (family 278) with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#5" class="mim-tip-reference" title="Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. <strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong> Am. J. Hum. Genet. 71: 518-527, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145748">Eymard-Pierre et al. (2002)</a> found a homozygous 2-bp deletion at nucleotide 1130 (1130delAT) in exon 4 of both the short and the long ALS2 transcripts. The deletion led to a frameshift and a premature translation termination at amino acid 335. Both parents and an unaffected sib were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145748" 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="0009" class="mim-anchor"></a>
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<h4>
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<strong>.0009 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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</h4>
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ALS2, 1-BP DEL, 4844T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134188 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134188;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=rs386134188" 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=rs386134188" 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=RCV000004662" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004662" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004662</a>
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<p>In a large consanguineous Pakistani family with infantile-onset complicated spastic paraparesis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Meijer, I. A., Hand, C. K., Dube, M.-P., MacGregor, D. L., Seni, M.-H., Devon, R. S., Hayden, M. R., Andermann, F., Andermann, E., Rouleau, G. A. <strong>An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. (Letter)</strong> Ann. Neurol. 53: 144-145, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509863</a>] [<a href="https://doi.org/10.1002/ana.10422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12509863">Gros-Louis et al. (2003)</a> identified a 1-bp deletion (4844delT) in exon 32 of the ALS2 gene. The proband presented with gait disturbance and hyperreflexia at 18 months and was anarthric and wheelchair-bound by age 12 years. Family history indicated that the disease slowly progressed to tetraplegia and death by the fourth decade, with relatively preserved intellect. The mutation cosegregated with the disease in the family and was absent in 155 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12509863" 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 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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ALS2, ARG998TER
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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> rs121908137 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908137;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/rs121908137?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=rs121908137" 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=rs121908137" 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=RCV000004663" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004663" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004663</a>
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<p>In 2 sisters, born of first-cousin Buchari Jewish parents, with infantile-onset ascending spastic paraplegia (IAHSP; <a href="/entry/607225">607225</a>) with bulbar involvement, <a href="#3" class="mim-tip-reference" title="Devon, R. S., Helm, J. R., Rouleau, G. A., Leitner, Y., Lerman-Sagie, T., Lev, D., Hayden, M. R. <strong>The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings.</strong> Clin. Genet. 64: 210-215, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919135</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00138.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919135">Devon et al. (2003)</a> found homozygosity for a 3115C-T transition in the ALS2 gene, predicted to result in a stop codon in place of an arginine at amino acid 998 (R998X). This sequence change would lead to premature termination of the protein with presumed loss of function. Both parents were heterozygous for the mutation. The clinical phenotype of the sisters was practically identical. Development was normal until 12 to 14 months of age, when signs of spasticity were noted. By 2 years of age, both sisters showed spasticity in the arms. By 3 years of age, 1 sister developed supranuclear bulbar palsy, which included involuntary laughing, hyperactive gag and jaw jerk reflexes, and progressive dysarthria. At 6 years of age, the other sister had pseudobulbar palsy with a weak and dysarthric voice that was hard to comprehend. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<strong>.0011 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</strong>
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ALS2, 1-BP DEL, 553A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134174;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=rs386134174" 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=rs386134174" 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=RCV000004664 OR RCV000995489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004664, RCV000995489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004664...</a>
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<p>In a Turkish man, born of consanguineous parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; <a href="/entry/205100">205100</a>), <a href="#16" class="mim-tip-reference" title="Kress, J. A., Kuhnlein, P., Winter, P., Ludolph, A. C., Kassubek, J., Muller, U., Sperfeld, A.-D. <strong>Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis.</strong> Ann. Neurol. 58: 800-803, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240357</a>] [<a href="https://doi.org/10.1002/ana.20665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240357">Kress et al. (2005)</a> identified a homozygous 1-bp deletion (553delA) in exon 4 of the ALS2 gene, resulting in a frameshift and premature termination of the protein at residue 189. The mutation affects both the long and short forms of the protein. The patient had a severe disease course; onset occurred at age 2 years and he was wheelchair-bound by age 16. The patient's unaffected parents and 2 unaffected brothers were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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ALS2, CYS156TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908138 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908138;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=rs121908138" 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=rs121908138" 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=RCV000004665 OR RCV001090658" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004665, RCV001090658" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004665...</a>
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<p>In 2 affected sisters with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), born of consanguineous Turkish parents, <a href="#6" class="mim-tip-reference" title="Eymard-Pierre, E., Yamanaka, K., Haeussler, M., Kress, W., Gauthier-Barichard, F., Combes, P., Cleveland, D. W., Boespflug-Tanguy, O. <strong>Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.</strong> Ann. Neurol. 59: 976-980, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16718699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16718699</a>] [<a href="https://doi.org/10.1002/ana.20879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16718699">Eymard-Pierre et al. (2006)</a> identified a homozygous 669G-A transition in exon 4 of the ALS2 gene, resulting in a cys156-to-tyr (C156Y) substitution in a highly conserved residue in the RCC1-like domain. Immunoblot analysis showed absence of the ALS2 protein in patient lymphoblasts. Functional expression studies in HEK293 cells showed decreased stability of the mutant protein and loss of ALS2 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16718699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0013 PRIMARY LATERAL SCLEROSIS, JUVENILE</strong>
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</h4>
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ALS2, IVS17AS, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134184;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=rs386134184" 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=rs386134184" 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=RCV000004666" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004666" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004666</a>
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<p>In 3 affected members of a consanguineous Cypriot family with juvenile primary lateral sclerosis (PLSJ; <a href="/entry/606353">606353</a>), <a href="#18" class="mim-tip-reference" title="Mintchev, N., Zamba-Papanicolaou, E., Kleopa, K. A., Christodoulou, K. <strong>A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family.</strong> Neurology 72: 28-32, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19122027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19122027</a>] [<a href="https://doi.org/10.1212/01.wnl.0000338530.77394.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19122027">Mintchev et al. (2009)</a> identified a homozygous A-to-G transition in intron 17 of the ALS2 gene, resulting in the loss of exon 18 and premature termination. Onset was at age 2 years, with leg spasticity, bulbar paresis, and prominent saccadic gaze paresis. One patient became wheelchair-bound at age 50 years, the second never achieved ambulation, and the third remained ambulatory at age 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19122027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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</span>
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</h4>
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ALS2, GLN715TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908139;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=rs121908139" 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=rs121908139" 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=RCV000004667" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004667" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004667</a>
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</span>
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<p>In 2 Dutch sibs, born of consanguineous parents, with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#24" class="mim-tip-reference" title="Verschuuren-Bemelmans, C. C., Winter, P., Sival, D. A., Elting, J.-W., Brouwer, O. F., Muller, U. <strong>Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe.</strong> Europ. J. Hum. Genet. 16: 1407-1411, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18523452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18523452</a>] [<a href="https://doi.org/10.1038/ejhg.2008.108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18523452">Verschuuren-Bemelmans et al. (2008)</a> identified a homozygous 2143C-T transition in exon 10 of the ALS2 gene, resulting in a gln715-to-ter (Q715X) substitution, predicted to result in a truncated protein. The unaffected parents were each heterozygous for the mutation. The parents were descended from a common ancestor who lived during the 18th century in the province of Friesland, in the northern part of the Netherlands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18523452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
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</span>
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</h4>
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ALS2, ARG921TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777132 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777132;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=rs587777132" 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=rs587777132" 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=RCV000087053 OR RCV000171328 OR RCV001095478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087053, RCV000171328, RCV001095478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087053...</a>
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</span>
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<div>
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<p>In 2 sibs, born of consanguineous Saudi parents, with infantile-onset ascending spastic paralysis (IAHSP; <a href="/entry/607225">607225</a>), <a href="#25" class="mim-tip-reference" title="Wakil, S. M., Ramzan, K., Abuthuraya, R., Hagos, S., Al-Dossari, H., Al-Omar, R., Murad, H., Chedrawi, A., Al-Hassnan, Z. N., Finsterer, J., Bohlega, S. <strong>Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C-T.</strong> Gene 536: 217-220, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24315819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24315819</a>] [<a href="https://doi.org/10.1016/j.gene.2013.11.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24315819">Wakil et al. (2014)</a> identified a homozygous c.2761C-T transition in exon 15 of the ALS2 gene, resulting in an arg921-to-ter (R921X) substitution in the pleckstrin domain. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. It was not present in 184 Saudi controls. After normal early development, both patients developed progressive spastic paraplegia around the age of walking and became wheelchair-bound in mid-childhood. Other features included spastic anarthria and swallowing difficulties; cognition was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24315819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<h4>
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<strong>.0016 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</strong>
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</span>
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</h4>
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ALS2, GLY668TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs730882255 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882255;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=rs730882255" 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=rs730882255" 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=RCV000162071" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162071" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162071</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous Bangladeshi parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; <a href="/entry/205100">205100</a>), <a href="#23" class="mim-tip-reference" title="Sheerin, U.-M., Schneider, S. A., Carr, L., Deuschl, G., Hopfner, F., Stamelou, M., Wood, N. W., Bhatia, K. P. <strong>ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia.</strong> Neurology 82: 1065-1067, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24562058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24562058</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24562058">Sheerin et al. (2014)</a> identified a homozygous c.2002G-T transversion in the ALS2 gene, resulting in a gly668-to-ter (G668X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies were not performed. In addition to ALS, both patients had dystonia, nystagmus, and microcephaly, and 1 had ataxia. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24562058" 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>.0017 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</strong>
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ALS2, 1-BP DUP, 4573G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs730882256 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882256;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=rs730882256" 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=rs730882256" 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=RCV000162072 OR RCV001089474" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162072, RCV001089474" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162072...</a>
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<p>In 2 sibs, born of consanguineous Turkish parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; <a href="/entry/205100">205100</a>), <a href="#23" class="mim-tip-reference" title="Sheerin, U.-M., Schneider, S. A., Carr, L., Deuschl, G., Hopfner, F., Stamelou, M., Wood, N. W., Bhatia, K. P. <strong>ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia.</strong> Neurology 82: 1065-1067, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24562058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24562058</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24562058">Sheerin et al. (2014)</a> identified a homozygous 1-bp duplication (c.4573dupG) in the ALS2 gene, resulting in a frameshift and premature termination (Val1525fs). The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server database. In addition to ALS, both patients had generalized dystonia. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24562058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Al-Chalabi2003" class="mim-anchor"></a>
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Al-Chalabi, A., Hansen, V. K., Simpson, C. L., Xi, J., Hosler, B. A., Powell, J. F., McKenna-Yasek, D., Shaw, C. E., Leigh, P. N., Brown, R. H., Jr.
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<strong>Variants in the ALS2 gene are not associated with sporadic amyotrophic lateral sclerosis. (Letter)</strong>
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Neurogenetics 4: 221-222, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12768434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12768434</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12768434" 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/s10048-003-0152-1" target="_blank">Full Text</a>]
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<a id="Ben Hamida1990" class="mim-anchor"></a>
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Ben Hamida, M., Hentati, F., Ben Hamida, C.
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<strong>Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy.</strong>
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Brain 113: 347-363, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2328408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2328408</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2328408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/113.2.347" target="_blank">Full Text</a>]
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Devon, R. S., Helm, J. R., Rouleau, G. A., Leitner, Y., Lerman-Sagie, T., Lev, D., Hayden, M. R.
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<strong>The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings.</strong>
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Clin. Genet. 64: 210-215, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919135</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919135" 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/10.1034/j.1399-0004.2003.00138.x" target="_blank">Full Text</a>]
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<a id="Devon2006" class="mim-anchor"></a>
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Devon, R. S., Orban, P. C., Gerrow, K., Barbieri, M. A., Schwab, C., Cao, L. P., Helm, J. R., Bissada, N., Cruz-Aguado, R., Davidson, T.-L., Witmer, J., Metzler, M., Lam, C. K., Tetzlaff, W., Simpson, E. M., McCaffery, J. M., El-Husseini, A. E., Leavitt, B. R., Hayden, M. R.
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<strong>Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.</strong>
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Proc. Nat. Acad. Sci. 103: 9595-9600, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16769894[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=16769894" 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.0510197103" target="_blank">Full Text</a>]
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Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O.
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<strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong>
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Am. J. Hum. Genet. 71: 518-527, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145748</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145748[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=12145748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/342359" target="_blank">Full Text</a>]
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Eymard-Pierre, E., Yamanaka, K., Haeussler, M., Kress, W., Gauthier-Barichard, F., Combes, P., Cleveland, D. W., Boespflug-Tanguy, O.
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<strong>Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.</strong>
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Ann. Neurol. 59: 976-980, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16718699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16718699</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16718699" 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/ana.20879" target="_blank">Full Text</a>]
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<a id="Gros-Louis2003" class="mim-anchor"></a>
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Gros-Louis, F., Meijer, I. A., Hand, C. K., Dube, M.-P., MacGregor, D. L., Seni, M.-H., Devon, R. S., Hayden, M. R., Andermann, F., Andermann, E., Rouleau, G. A.
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<strong>An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. (Letter)</strong>
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Ann. Neurol. 53: 144-145, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12509863" 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/ana.10422" target="_blank">Full Text</a>]
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<a id="Hadano2006" class="mim-anchor"></a>
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<div class="">
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Hadano, S., Benn, S. C., Kakuta, S., Otomo, A., Sudo, K., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Shefner, J. M., Cox, G. A., Iwakura, Y., Brown, R. H., Jr., Ikeda, J.-E.
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<strong>Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking.</strong>
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Hum. Molec. Genet. 15: 233-250, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321985" 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/ddi440" target="_blank">Full Text</a>]
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<a id="Hadano2001" class="mim-anchor"></a>
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Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others.
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<strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong>
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Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586298" 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/ng1001-166" target="_blank">Full Text</a>]
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Hadano, S.
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<strong>Personal Communication.</strong>
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Isehara, Japan 3/11/2002.
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Hand, C. K., Devon, R. S., Gros-Louis, F., Rochefort, D., Khoris, J., Meininger, V., Bouchard, J.-P., Camu, W., Hayden, M. R., Rouleau, G. A.
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<strong>Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis.</strong>
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Arch. Neurol. 60: 1768-1771, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676054</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676054" 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.60.12.1768" target="_blank">Full Text</a>]
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<a id="Hentati1994" class="mim-anchor"></a>
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Hentati, A., Bejaoui, K., Pericak-Vance, M. A., Hentati, F., Speer, M. C., Hung, W.-Y., Figlewicz, D. A., Haines, J., Rimmler, J., Ben Hamida, C., Ben Hamida, M., Brown, R. H. Jr., Siddique, T.
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<strong>Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.</strong>
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Nature Genet. 7: 425-428, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7920663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7920663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7920663" 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/ng0794-425" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp136" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M313236200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20665" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/088307389601100114" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000338530.77394.60" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg184" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2008.01.177" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24562058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24562058</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24562058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000000254" target="_blank">Full Text</a>]
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<strong>Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe.</strong>
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[<a href="https://doi.org/10.1016/j.gene.2013.11.043" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20888" target="_blank">Full Text</a>]
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Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T.
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<strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586297</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586297" 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/ng1001-160" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 2/25/2015
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<div class="row collapse" id="mimCollapseContributors">
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Cassandra L. Kniffin - updated : 2/19/2014<br>George E. Tiller - updated : 2/25/2010<br>Cassandra L. Kniffin - updated : 10/29/2009<br>Cassandra L. Kniffin - updated : 8/31/2009<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Patricia A. Hartz - updated : 7/19/2006<br>Cassandra L. Kniffin - updated : 3/7/2006<br>George E. Tiller - updated : 5/5/2005<br>Cassandra L. Kniffin - updated : 2/24/2004<br>Victor A. McKusick - updated : 10/16/2003<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 5/27/2003<br>Victor A. McKusick - updated : 9/17/2002
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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 : 10/3/2001
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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 : 11/09/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 11/08/2023<br>carol : 02/21/2020<br>carol : 08/17/2015<br>carol : 3/2/2015<br>mcolton : 2/25/2015<br>ckniffin : 2/25/2015<br>carol : 2/21/2014<br>mcolton : 2/20/2014<br>ckniffin : 2/19/2014<br>carol : 9/16/2013<br>wwang : 3/11/2010<br>terry : 2/25/2010<br>wwang : 11/5/2009<br>ckniffin : 10/29/2009<br>wwang : 9/16/2009<br>ckniffin : 8/31/2009<br>wwang : 3/26/2009<br>ckniffin : 3/16/2009<br>wwang : 9/25/2007<br>ckniffin : 9/18/2007<br>ckniffin : 9/18/2007<br>mgross : 7/20/2006<br>terry : 7/19/2006<br>carol : 3/10/2006<br>carol : 3/10/2006<br>ckniffin : 3/7/2006<br>tkritzer : 5/5/2005<br>tkritzer : 2/24/2004<br>cwells : 10/20/2003<br>terry : 10/16/2003<br>tkritzer : 10/15/2003<br>tkritzer : 10/13/2003<br>tkritzer : 6/9/2003<br>ckniffin : 5/27/2003<br>alopez : 9/18/2002<br>carol : 9/17/2002<br>alopez : 3/13/2002<br>alopez : 3/13/2002<br>carol : 2/4/2002<br>alopez : 11/5/2001<br>alopez : 10/3/2001<br>alopez : 10/3/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606352
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<div>
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<h3>
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<span class="mim-font">
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ALSIN RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR ALS2; ALS2
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</h3>
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<div>
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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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ALSIN<br />
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ALS2 GENE<br />
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KIAA1563
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</h4>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ALS2</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 703543005, 717964007;
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 2q33.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:201,700,267-201,780,933 </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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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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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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</th>
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<th>
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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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<td rowspan="3">
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<span class="mim-font">
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2q33.1
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<span class="mim-font">
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Amyotrophic lateral sclerosis 2, juvenile
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<span class="mim-font">
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205100
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<span class="mim-font">
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Autosomal recessive
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Primary lateral sclerosis, juvenile
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<span class="mim-font">
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606353
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<span class="mim-font">
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Autosomal recessive
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Spastic paralysis, infantile onset ascending
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</td>
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<span class="mim-font">
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607225
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</table>
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<br />
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Alsin, which is encoded by the ALS2 gene, is a member of the guanine nucleotide exchange factors for the small GTPase RAB5 (179512) and plays a role in intracellular endosomal trafficking (summary by Hadano et al., 2006). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By positional cloning, Yang et al. (2001) and Hadano et al. (2001) isolated a gene found to be mutant in families with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100) or juvenile primary lateral sclerosis (PLSJ; 606353). The coding sequence gives rise to a deduced 184-kD 1,657-residue long form of the protein, and alternative splicing after exon 4 yields a 396-residue short form. Yang et al. (2001) and Hadano et al. (2001) both determined that the deduced ALS2 protein contains several guanine-nucleotide exchange factor domains, consistent with a function in cell signaling. By Northern blot analysis, Yang et al. (2001) detected 2 mRNA bands of 2.3 and 6 kb, whereas Hadano et al. (2001) reported mRNA bands of 2.6 and 6.5 kb. The ALS2 gene is expressed in various tissues and cells, including neurons throughout the brain and spinal cord. It was found to be identical to KIAA1563, identified by Nagase et al. (2000). </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>Yang et al. (2001) and Hadano et al. (2001) independently determined that the ALS2 gene comprises 34 exons in a genomic region of 83 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>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>Otomo et al. (2003) showed that the ALS2 protein specifically binds to small GTPase RAB5 (179512) and functions as a guanine nucleotide exchange factor (GEF) for RAB5. Ectopically expressed ALS2 localized with RAB5 and early endosome antigen-1 (EEA1; 605070) onto early endosomal compartments and stimulated the enlargement of endosomes in cultured cortical neurons. The C terminus of ALS2 carrying a VPS9 domain mediated not only the activation of RAB5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of ALS2, whereas the N-terminal region containing the RCC1 (179710)-like domain acted suppressive in its membranous localization. The DH/PH domain in the middle portion of ALS2 enhanced the VPS9 domain-mediated endosome fusions. Otomo et al. (2003) hypothesized that a perturbation of endosomal dynamics caused by loss of the ALS2 functional domain that confers RAB5 GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases. </p><p>Kanekura et al. (2004) found that the long 1,657-residue isoform of ALS2 bound to mutant SOD1 (147450) via the RhoGEF domain and protected mouse motor neurons from toxicity induced by mutant SOD1. In contrast, the short 396-residue isoform of ALS2 and truncating pathogenic ALS2 mutations did not protect mouse neurons from mutant SOD1 toxicity. The long isoform of ALS2 did not bind to wildtype SOD1, but the short ALS2 isoform did bind to wildtype SOD1. Further studies indicated that the C-terminal region of ALS2 prevents the long isoform from binding to wildtype SOD1. The long isoform of ALS2 did not protect neurons against other non-ALS insults, such as mutant PS1 (104311), SNCA (163890), or APP (104760). The findings suggested a functional link between 2 ALS-related genes. </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>Among 3 families reported by Yang et al. (2001) and Hadano et al. (2001), 1 had a 1-bp deletion in exon 3 (606352.0001) of the ALS2 gene, which resulted in the more severe juvenile ALS phenotype, whereas 2 had 2-bp deletions in exons 9 and 5 of the ALS2 gene, (606352.0002; 606352.0004), respectively, which resulted in the milder juvenile primary lateral sclerosis phenotype. The authors suggested that the milder PLSJ phenotype may have occurred because of an intact short protein or some preservation of function of the mutated longer protein. The truncating nature of the mutations and the recessive pattern of inheritance suggested that motor neuron degeneration is the result of a loss of function. </p><p>Eymard-Pierre et al. (2002) identified homozygous mutations in the ALS2 gene (606352.0005-606352.0008) in affected members of 4 of 10 families with infantile-onset ascending spastic paralysis (IAHSP; 607225). All the mutations led to a truncated alsin protein. The authors noted that ALS2 mutations are responsible for a primitive, retrograde degeneration of the upper motor neurons of the pyramidal tracts, resulting in a clinical continuum from infantile (IAHSP) to juvenile forms with (ALS2) or without (PLSJ) lower motor neuron involvement. </p><p>Al-Chalabi et al. (2003) stated that 7 mutations in the ALS2 gene had been reported in association with various forms of ALS. However, Al-Chalabi et al. (2003) found no significant association between variants in the ALS2 gene and sporadic ALS (see 105400). The authors concluded that variants of the ALS2 gene are not a common cause of a predominantly early-onset, upper motor neuron disease phenotype of sporadic ALS, nor are they associated with a more typical phenotype. </p><p>Among 201 patients with familial, sporadic, or early-onset ALS, Hand et al. (2003) found no pathogenic mutations in the ALS2 gene, suggesting that mutations in the ALS2 gene are not a common cause of ALS. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Devon et al. (2006) found that Als2-null mice were born in the expected mendelian ratio and were indistinguishable from their wildtype littermates in size, appearance, and overall behavior. Als2 deficiency did not affect fertility or fecundity. However, Als2-deficient mice exhibited significant but subtle neuropathologic changes. Cytosol from brains of Als2-null mice showed marked diminution of Rab5-dependent endosome fusion activity. Primary neurons from Als2-null mice showed a disturbance in endosomal transport of Igf1 receptor (IGF1R; 147370) and Bdnf receptor (NTRK2; 600456), whereas neuronal viability and endocytosis of transferrin (TF; 190000) and dextran seemed unaltered. There was a significant decrease in the size of cortical motor neurons, and Als2-null mice were mildly hypoactive. </p><p>Yamanaka et al. (2006) found that Als2-null mice showed progressive axonal degeneration in the lateral spinal cord that was also prominent in mutant SOD1 (147450) mice, a model for human ALS. Lower motor neurons were preserved in Als2-null mice, a finding that is distinct from classic ALS, which shows both upper and lower motor neuron involvement. Phenotypically, Als2-null mice showed slowed movement without muscle weakness, consistent with upper motor neuron defects that lead to spasticity in humans. </p><p>Hadano et al. (2006) found that Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiologic analyses showed an age-dependent, slowly progressive loss of cerebellar Purkinje cells, a disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, and a progressive loss of motor axons, indicating a subclinical dysfunction of the motor system in Als2-null mice. Quantitative EGF-uptake analysis showed significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of intracellular endosome/vesicle trafficking. Overall, however, the mice did not show a profound defect in motor performance, as seen in humans. </p><p>Otomo et al. (2008) found that hippocampal neurons from Als2-null mice had a delay in axon outgrowth and decreased macropinocytosis. Als2 colocalized with F-actin in vesicles and in membrane ruffles at the edge of growth cones in sprouting neurites. Axon outgrowth was delayed, but did occur, in Als2-null cells, and the survival rate of the cells was not affected. Otomo et al. (2008) suggested that ALS2 may act as a modulator in neuronal differentiation or development through regulation of membrane dynamics. </p><p>Jacquier et al. (2009) demonstrated that alsin-depleted murine spinal motor neurons could be rescued from defective survival and axon growth by cocultured astrocytes. The astrocytic rescue was mediated by an unidentified soluble protective factor rather than by cellular contact. Cortical neurons were intrinsically as vulnerable to alsin depletion as spinal motor neurons, but could not be rescued by cocultured astrocytes. </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>17 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</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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ALS2, 1-BP DEL, 138A
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<br />
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SNP: rs386134173,
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ClinVar: RCV000004655
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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 a Tunisian family with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100) reported by Ben Hamida et al. (1990) and Hentati et al. (1992, 1994), Yang et al. (2001) and Hadano et al. (2001) identified a homozygous 1-bp deletion (138delA) in exon 3 of the ALS2 gene, resulting in a frameshift and a premature stop codon 4 codons after the deletion site. The 1-bp deletion occurred in codon 46 for alanine and the premature stop was at codon 50. The deletion affected both the long and short forms of the protein. The mutation was not identified in 533 control individuals (Hadano et al., 2001). </p><p>Hadano (2002) pointed out that this mutation, which Hadano et al. (2001) identified as 261delA, should be referred to as 138delA. </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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<h4>
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<span class="mim-font">
|
|
<strong>.0002 PRIMARY LATERAL SCLEROSIS, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 2-BP DEL, 1867CT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134181,
|
|
|
|
|
|
gnomAD: rs386134181,
|
|
|
|
|
|
ClinVar: RCV000004656, RCV000995486
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a consanguineous Saudi Arabian family with juvenile primary lateral sclerosis (PLSJ; 606353), Yang et al. (2001) identified a homozygous 2-bp deletion (1867delCT) in exon 9 of the ALS2 gene. This deletion led to a frameshift and premature stop codon 23 codons after the deletion site. A deletion occurred in codon 623 for leucine and the premature stop was created at codon 646. </p>
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0003 MOVED TO 606352.0001</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PRIMARY LATERAL SCLEROSIS, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 2-BP DEL, 1425AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134176,
|
|
|
|
|
|
|
|
ClinVar: RCV000004657, RCV004799732
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Kuwaiti family reported by Lerman-Sagie et al. (1996) in which affected members showed early development of progressive spasticity but no evidence of denervation in the first 2 decades of life, Hadano et al. (2001) identified a homozygous 2-bp deletion (1425delAG) in exon 5 of the ALS2 gene. Shaw (2001) classified this family as having primary lateral sclerosis (PLSJ; 606353) because of the lack of evidence of denervation. </p><p>In a personal communication, Hadano (2002) pointed out that the mutation identified by Hadano et al. (2001) as 1548delAG should be referred to as 1425delAG. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 1-BP DEL, 3742A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134187,
|
|
|
|
|
|
|
|
ClinVar: RCV000004658
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a family (family 362) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 1-bp deletion (3742delA) in exon 22 in the long ALS2 transcript, causing a frameshift and a stop codon at met1206. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 10-BP DEL, NT1471
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906316,
|
|
|
|
|
|
|
|
ClinVar: RCV000004659
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (family 419) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 10-bp deletion at nucleotide 1471 in exon 6 of the long ALS2 transcript. The deletion led to a frameshift and a premature stop codon at amino acid 493. Genomic DNA analysis with primers amplifying exon 6 and the corresponding splice site regions demonstrated a homozygous point mutation (G to T) in the consensus CAG acceptor splice site of exon 6. Both parents and 1 unaffected sib were heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 2-BP DEL, 2660AT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134183,
|
|
|
|
|
|
|
|
ClinVar: RCV000004660
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (family 283) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 2-bp deletion at nucleotide 2660 (2660delAT) in exon 13 of the long ALS2 transcript. The deletion led to a frameshift at asn845 and a premature stop codon 12 codons after the deletion site at amino acid 858. The parents for heterozygous for the mutation, and an unaffected brother was homozygous for the normal allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 2-BP DEL, 1130AT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134175,
|
|
|
|
|
|
|
|
ClinVar: RCV000004661
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (family 278) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 2-bp deletion at nucleotide 1130 (1130delAT) in exon 4 of both the short and the long ALS2 transcripts. The deletion led to a frameshift and a premature translation termination at amino acid 335. Both parents and an unaffected sib were heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 1-BP DEL, 4844T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134188,
|
|
|
|
|
|
|
|
ClinVar: RCV000004662
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large consanguineous Pakistani family with infantile-onset complicated spastic paraparesis (IAHSP; 607225), Gros-Louis et al. (2003) identified a 1-bp deletion (4844delT) in exon 32 of the ALS2 gene. The proband presented with gait disturbance and hyperreflexia at 18 months and was anarthric and wheelchair-bound by age 12 years. Family history indicated that the disease slowly progressed to tetraplegia and death by the fourth decade, with relatively preserved intellect. The mutation cosegregated with the disease in the family and was absent in 155 control individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, ARG998TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908137,
|
|
|
|
|
|
gnomAD: rs121908137,
|
|
|
|
|
|
ClinVar: RCV000004663
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters, born of first-cousin Buchari Jewish parents, with infantile-onset ascending spastic paraplegia (IAHSP; 607225) with bulbar involvement, Devon et al. (2003) found homozygosity for a 3115C-T transition in the ALS2 gene, predicted to result in a stop codon in place of an arginine at amino acid 998 (R998X). This sequence change would lead to premature termination of the protein with presumed loss of function. Both parents were heterozygous for the mutation. The clinical phenotype of the sisters was practically identical. Development was normal until 12 to 14 months of age, when signs of spasticity were noted. By 2 years of age, both sisters showed spasticity in the arms. By 3 years of age, 1 sister developed supranuclear bulbar palsy, which included involuntary laughing, hyperactive gag and jaw jerk reflexes, and progressive dysarthria. At 6 years of age, the other sister had pseudobulbar palsy with a weak and dysarthric voice that was hard to comprehend. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, 1-BP DEL, 553A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134174,
|
|
|
|
|
|
|
|
ClinVar: RCV000004664, RCV000995489
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish man, born of consanguineous parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Kress et al. (2005) identified a homozygous 1-bp deletion (553delA) in exon 4 of the ALS2 gene, resulting in a frameshift and premature termination of the protein at residue 189. The mutation affects both the long and short forms of the protein. The patient had a severe disease course; onset occurred at age 2 years and he was wheelchair-bound by age 16. The patient's unaffected parents and 2 unaffected brothers were heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, CYS156TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908138,
|
|
|
|
|
|
|
|
ClinVar: RCV000004665, RCV001090658
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected sisters with infantile-onset ascending spastic paralysis (IAHSP; 607225), born of consanguineous Turkish parents, Eymard-Pierre et al. (2006) identified a homozygous 669G-A transition in exon 4 of the ALS2 gene, resulting in a cys156-to-tyr (C156Y) substitution in a highly conserved residue in the RCC1-like domain. Immunoblot analysis showed absence of the ALS2 protein in patient lymphoblasts. Functional expression studies in HEK293 cells showed decreased stability of the mutant protein and loss of ALS2 activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PRIMARY LATERAL SCLEROSIS, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, IVS17AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134184,
|
|
|
|
|
|
|
|
ClinVar: RCV000004666
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a consanguineous Cypriot family with juvenile primary lateral sclerosis (PLSJ; 606353), Mintchev et al. (2009) identified a homozygous A-to-G transition in intron 17 of the ALS2 gene, resulting in the loss of exon 18 and premature termination. Onset was at age 2 years, with leg spasticity, bulbar paresis, and prominent saccadic gaze paresis. One patient became wheelchair-bound at age 50 years, the second never achieved ambulation, and the third remained ambulatory at age 16. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, GLN715TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908139,
|
|
|
|
|
|
|
|
ClinVar: RCV000004667
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Dutch sibs, born of consanguineous parents, with infantile-onset ascending spastic paralysis (IAHSP; 607225), Verschuuren-Bemelmans et al. (2008) identified a homozygous 2143C-T transition in exon 10 of the ALS2 gene, resulting in a gln715-to-ter (Q715X) substitution, predicted to result in a truncated protein. The unaffected parents were each heterozygous for the mutation. The parents were descended from a common ancestor who lived during the 18th century in the province of Friesland, in the northern part of the Netherlands. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALS2, ARG921TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777132,
|
|
|
|
|
|
|
|
ClinVar: RCV000087053, RCV000171328, RCV001095478
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Saudi parents, with infantile-onset ascending spastic paralysis (IAHSP; 607225), Wakil et al. (2014) identified a homozygous c.2761C-T transition in exon 15 of the ALS2 gene, resulting in an arg921-to-ter (R921X) substitution in the pleckstrin domain. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. It was not present in 184 Saudi controls. After normal early development, both patients developed progressive spastic paraplegia around the age of walking and became wheelchair-bound in mid-childhood. Other features included spastic anarthria and swallowing difficulties; cognition was normal. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
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<span class="mim-text-font">
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ALS2, GLY668TER
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<br />
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SNP: rs730882255,
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ClinVar: RCV000162071
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous Bangladeshi parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Sheerin et al. (2014) identified a homozygous c.2002G-T transversion in the ALS2 gene, resulting in a gly668-to-ter (G668X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies were not performed. In addition to ALS, both patients had dystonia, nystagmus, and microcephaly, and 1 had ataxia. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE</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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ALS2, 1-BP DUP, 4573G
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<br />
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SNP: rs730882256,
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ClinVar: RCV000162072, RCV001089474
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous Turkish parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Sheerin et al. (2014) identified a homozygous 1-bp duplication (c.4573dupG) in the ALS2 gene, resulting in a frameshift and premature termination (Val1525fs). The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server database. In addition to ALS, both patients had generalized dystonia. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Al-Chalabi, A., Hansen, V. K., Simpson, C. L., Xi, J., Hosler, B. A., Powell, J. F., McKenna-Yasek, D., Shaw, C. E., Leigh, P. N., Brown, R. H., Jr.
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<strong>Variants in the ALS2 gene are not associated with sporadic amyotrophic lateral sclerosis. (Letter)</strong>
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Neurogenetics 4: 221-222, 2003.
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<p class="mim-text-font">
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Ben Hamida, M., Hentati, F., Ben Hamida, C.
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<strong>Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy.</strong>
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Brain 113: 347-363, 1990.
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[PubMed: 2328408]
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[Full Text: https://doi.org/10.1093/brain/113.2.347]
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<p class="mim-text-font">
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Devon, R. S., Helm, J. R., Rouleau, G. A., Leitner, Y., Lerman-Sagie, T., Lev, D., Hayden, M. R.
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<strong>The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings.</strong>
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Clin. Genet. 64: 210-215, 2003.
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[PubMed: 12919135]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00138.x]
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<p class="mim-text-font">
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Devon, R. S., Orban, P. C., Gerrow, K., Barbieri, M. A., Schwab, C., Cao, L. P., Helm, J. R., Bissada, N., Cruz-Aguado, R., Davidson, T.-L., Witmer, J., Metzler, M., Lam, C. K., Tetzlaff, W., Simpson, E. M., McCaffery, J. M., El-Husseini, A. E., Leavitt, B. R., Hayden, M. R.
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<strong>Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.</strong>
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Proc. Nat. Acad. Sci. 103: 9595-9600, 2006.
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[PubMed: 16769894]
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[Full Text: https://doi.org/10.1073/pnas.0510197103]
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<p class="mim-text-font">
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Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., Boespflug-Tanguy, O.
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<strong>Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.</strong>
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Am. J. Hum. Genet. 71: 518-527, 2002.
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[PubMed: 12145748]
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[Full Text: https://doi.org/10.1086/342359]
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<li>
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<p class="mim-text-font">
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Eymard-Pierre, E., Yamanaka, K., Haeussler, M., Kress, W., Gauthier-Barichard, F., Combes, P., Cleveland, D. W., Boespflug-Tanguy, O.
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<strong>Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.</strong>
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Ann. Neurol. 59: 976-980, 2006.
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[PubMed: 16718699]
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[Full Text: https://doi.org/10.1002/ana.20879]
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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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Gros-Louis, F., Meijer, I. A., Hand, C. K., Dube, M.-P., MacGregor, D. L., Seni, M.-H., Devon, R. S., Hayden, M. R., Andermann, F., Andermann, E., Rouleau, G. A.
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<strong>An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. (Letter)</strong>
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Ann. Neurol. 53: 144-145, 2003.
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[PubMed: 12509863]
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[Full Text: https://doi.org/10.1002/ana.10422]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hadano, S., Benn, S. C., Kakuta, S., Otomo, A., Sudo, K., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Shefner, J. M., Cox, G. A., Iwakura, Y., Brown, R. H., Jr., Ikeda, J.-E.
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|
<strong>Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking.</strong>
|
|
Hum. Molec. Genet. 15: 233-250, 2006.
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[PubMed: 16321985]
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[Full Text: https://doi.org/10.1093/hmg/ddi440]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others.
|
|
<strong>A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.</strong>
|
|
Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.
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[PubMed: 11586298]
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[Full Text: https://doi.org/10.1038/ng1001-166]
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</p>
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<li>
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<p class="mim-text-font">
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|
Hadano, S.
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<strong>Personal Communication.</strong>
|
|
Isehara, Japan 3/11/2002.
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</p>
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<li>
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<p class="mim-text-font">
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Hand, C. K., Devon, R. S., Gros-Louis, F., Rochefort, D., Khoris, J., Meininger, V., Bouchard, J.-P., Camu, W., Hayden, M. R., Rouleau, G. A.
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<strong>Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis.</strong>
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Arch. Neurol. 60: 1768-1771, 2003.
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[PubMed: 14676054]
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[Full Text: https://doi.org/10.1001/archneur.60.12.1768]
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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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Hentati, A., Bejaoui, K., Pericak-Vance, M. A., Hentati, F., Speer, M. C., Hung, W.-Y., Figlewicz, D. A., Haines, J., Rimmler, J., Ben Hamida, C., Ben Hamida, M., Brown, R. H. Jr., Siddique, T.
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<strong>Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.</strong>
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Nature Genet. 7: 425-428, 1994.
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[PubMed: 7920663]
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[Full Text: https://doi.org/10.1038/ng0794-425]
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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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Hentati, A., Bejaoui, K., Pericak-Vance, M. A., Hentati, F., Yen-Hung, W., Figlewicz, D. A., Ben Hamida, C., Ben Hamida, M., Brown, R. H., Jr., Siddique, T.
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<strong>The gene locus for one form of juvenile amyotrophic lateral sclerosis maps to chromosome 2. (Abstract)</strong>
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Am. J. Hum. Genet. 51 (suppl.): A33 only, 1992.
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<p class="mim-text-font">
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Jacquier, A., Bellouze, S., Blanchard, S., Bohl, D., Haase, G.
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<strong>Astrocytic protection of spinal motor neurons but not cortical neurons against loss of Als2/alsin function.</strong>
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Hum. Molec. Genet. 18: 2127-2139, 2009.
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[PubMed: 19304783]
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[Full Text: https://doi.org/10.1093/hmg/ddp136]
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<p class="mim-text-font">
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Kanekura, K., Hashimoto, Y., Niikura, T., Aiso, S., Matsuoka, M., Nishimoto, I.
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<strong>Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants.</strong>
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J. Biol. Chem. 279: 19247-19256, 2004.
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[PubMed: 14970233]
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[Full Text: https://doi.org/10.1074/jbc.M313236200]
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<p class="mim-text-font">
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Kress, J. A., Kuhnlein, P., Winter, P., Ludolph, A. C., Kassubek, J., Muller, U., Sperfeld, A.-D.
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<strong>Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis.</strong>
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Ann. Neurol. 58: 800-803, 2005.
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[PubMed: 16240357]
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<p class="mim-text-font">
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Lerman-Sagie, T., Filiano, J., Smith, D. W., Korson, M.
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<strong>Infantile onset of hereditary ascending spastic paralysis with bulbar involvement.</strong>
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J. Child. Neurol. 11: 54-57, 1996.
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[PubMed: 8745388]
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<p class="mim-text-font">
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Mintchev, N., Zamba-Papanicolaou, E., Kleopa, K. A., Christodoulou, K.
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<strong>A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family.</strong>
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Neurology 72: 28-32, 2009.
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[PubMed: 19122027]
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<p class="mim-text-font">
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Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
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<li>
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<p class="mim-text-font">
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|
Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., Showguchi-Miyata, J., Yanagisawa, Y., Kohiki, E., Suga, E., Yasuda, M., Osuga, H., Nishimoto, T., Narumiya, S., Ikeda, J.-E.
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<strong>ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.</strong>
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Hum. Molec. Genet. 12: 1671-1687, 2003.
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[PubMed: 12837691]
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</p>
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<li>
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<p class="mim-text-font">
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Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Mizumura, H., Onoe, K., Osuga, H., Hadano, S., Ikeda, J.-E.
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<strong>ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth.</strong>
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Biochem. Biophys. Res. Commun. 370: 87-92, 2008.
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[PubMed: 18358238]
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</p>
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<p class="mim-text-font">
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Shaw, P. J.
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<strong>Genetic inroads in familial ALS.</strong>
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Nature Genet. 29: 103-104, 2001.
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[PubMed: 11586285]
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[Full Text: https://doi.org/10.1038/ng1001-103]
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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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Sheerin, U.-M., Schneider, S. A., Carr, L., Deuschl, G., Hopfner, F., Stamelou, M., Wood, N. W., Bhatia, K. P.
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<strong>ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia.</strong>
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Neurology 82: 1065-1067, 2014.
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[PubMed: 24562058]
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[Full Text: https://doi.org/10.1212/WNL.0000000000000254]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Verschuuren-Bemelmans, C. C., Winter, P., Sival, D. A., Elting, J.-W., Brouwer, O. F., Muller, U.
|
|
<strong>Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe.</strong>
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|
Europ. J. Hum. Genet. 16: 1407-1411, 2008.
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[PubMed: 18523452]
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[Full Text: https://doi.org/10.1038/ejhg.2008.108]
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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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Wakil, S. M., Ramzan, K., Abuthuraya, R., Hagos, S., Al-Dossari, H., Al-Omar, R., Murad, H., Chedrawi, A., Al-Hassnan, Z. N., Finsterer, J., Bohlega, S.
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<strong>Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C-T.</strong>
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|
Gene 536: 217-220, 2014.
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[PubMed: 24315819]
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[Full Text: https://doi.org/10.1016/j.gene.2013.11.043]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Yamanaka, K., Miller, T. M., McAlonis-Downes, M., Chun, S. J., Cleveland, D. W.
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|
<strong>Progressive spinal axonal degeneration and slowness in ALS2-deficient mice.</strong>
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|
Ann. Neurol. 60: 95-104, 2006.
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|
[PubMed: 16802286]
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|
[Full Text: https://doi.org/10.1002/ana.20888]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T.
|
|
<strong>The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.</strong>
|
|
Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.
|
|
|
|
|
|
[PubMed: 11586297]
|
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[Full Text: https://doi.org/10.1038/ng1001-160]
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Cassandra L. Kniffin - updated : 2/25/2015<br>Cassandra L. Kniffin - updated : 2/19/2014<br>George E. Tiller - updated : 2/25/2010<br>Cassandra L. Kniffin - updated : 10/29/2009<br>Cassandra L. Kniffin - updated : 8/31/2009<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Patricia A. Hartz - updated : 7/19/2006<br>Cassandra L. Kniffin - updated : 3/7/2006<br>George E. Tiller - updated : 5/5/2005<br>Cassandra L. Kniffin - updated : 2/24/2004<br>Victor A. McKusick - updated : 10/16/2003<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 5/27/2003<br>Victor A. McKusick - updated : 9/17/2002
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Victor A. McKusick : 10/3/2001
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