5065 lines
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- *604581 - AFG3-LIKE MATRIX AAA PEPTIDASE, SUBUNIT 2; AFG3L2
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- OMIM
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<p>
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<span class="h4">*604581</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604581">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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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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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=ENSG00000141385;t=ENST00000269143" 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=10939" 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=604581" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000141385;t=ENST00000269143" 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_006796,XM_011525601" 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_006796" 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=604581" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05205&isoform_id=05205_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/AFG3L2" 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/5457357,18999411,40675546,119621956,119621957,126302516,300192933,767997555,2462559526" 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/Q9Y4W6" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=10939" 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=ENSG00000141385;t=ENST00000269143" 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=AFG3L2" 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=AFG3L2" 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+10939" 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/AFG3L2" 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:10939" 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/10939" 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=chr18&hgg_gene=ENST00000269143.8&hgg_start=12328944&hgg_end=12377227&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:315" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604581[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=604581[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/AFG3L2/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/ENSG00000141385" 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=AFG3L2" 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=AFG3L2" 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=AFG3L2" 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=AFG3L2&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/PA24612" 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:315" 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/FBgn0036702.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:1916847" 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/AFG3L2#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:1916847" 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/10939/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=10939" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004978;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070912-46" 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:10939" 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=AFG3L2&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> 715824008, 771469002<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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604581
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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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AFG3-LIKE MATRIX AAA PEPTIDASE, SUBUNIT 2; AFG3L2
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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">
|
|
ATPase FAMILY GENE 3-LIKE 2
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=AFG3L2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AFG3L2</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/18/63?start=-3&limit=10&highlight=63">18p11.21</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:12328944-12377227&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'})">18:12,328,944-12,377,227</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618977,614487,610246" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/18/63?start=-3&limit=10&highlight=63">
|
|
18p11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Optic atrophy 12
|
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|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618977"> 618977 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Spastic ataxia 5, autosomal recessive
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614487"> 614487 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 28
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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PheneGene Graphics <span class="caret"></span>
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<p>AFG3L2 is the catalytic subunit of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (summary by <a href="#11" class="mim-tip-reference" title="Koppen, M., Metodiev, M. D., Casari, G., Rugarli, E. I., Langer, T. <strong>Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia.</strong> Molec. Cell. Biol. 27: 758-767, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101804</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17101804[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01470-06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101804">Koppen et al., 2007</a>). AFG3L2 also regulates the processing of OPA1 (<a href="/entry/605290">605290</a>) through OMA1 (<a href="/entry/617081">617081</a>), which ultimately affects mitochondrial dynamics (summary by <a href="#1" class="mim-tip-reference" title="Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F. <strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong> Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32600459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32600459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32600459[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/10.1186/s40478-020-00975-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32600459">Baderna et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17101804+32600459" 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 searching an EST database with the sequence of paraplegin (SPG7; <a href="/entry/602783">602783</a>) and screening a fetal brain cDNA library, <a href="#2" class="mim-tip-reference" title="Banfi, S, Bassi, M. T., Andolfi, G., Marchitiello, A., Zanotta, S., Ballabio, A., Casari, G., Franco, B. <strong>Identification and characterization of AFG3L2, a novel paraplegin-related gene.</strong> Genomics 59: 51-58, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395799</a>] [<a href="https://doi.org/10.1006/geno.1999.5818" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395799">Banfi et al. (1999)</a> identified a cDNA for AFG3L2. AFG3L2 encodes a deduced 797-amino acid protein whose sequence shows 69% similarity to the yeast Afg3 mitochondrial ATPase and 49% identity to paraplegin. AFG3L2 contains an AAA (for ATPase associated with diverse cellular activities) domain of about 190 amino acids with an ATP/GTP-binding site, a zinc-dependent binding domain, and an RNA-binding region. Northern blot analysis revealed that AFG3L2 is expressed ubiquitously as a 3.2-kb transcript in fetal and adult tissues, with greatest expression in heart and skeletal muscle. Fluorescence microscopy showed that AFG3L2 is localized in mitochondria. Thus, AFG3L2 and paraplegin share a similar expression pattern and the same localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10395799" 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="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> noted that the AFG3L2 gene contains 17 exons spanning 48 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" 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 radiation hybrid analysis, <a href="#2" class="mim-tip-reference" title="Banfi, S, Bassi, M. T., Andolfi, G., Marchitiello, A., Zanotta, S., Ballabio, A., Casari, G., Franco, B. <strong>Identification and characterization of AFG3L2, a novel paraplegin-related gene.</strong> Genomics 59: 51-58, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395799</a>] [<a href="https://doi.org/10.1006/geno.1999.5818" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395799">Banfi et al. (1999)</a> mapped the AFG3L2 gene to chromosome 18p11. <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> noted that the AFG3L2 gene maps to chromosome 18p11.21. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20208537+10395799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using in vitro protein binding assays and immunoprecipitation analysis, <a href="#11" class="mim-tip-reference" title="Koppen, M., Metodiev, M. D., Casari, G., Rugarli, E. I., Langer, T. <strong>Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia.</strong> Molec. Cell. Biol. 27: 758-767, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101804</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17101804[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01470-06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101804">Koppen et al. (2007)</a> showed that paraplegin interacted with AFG3L2 in the m-AAA protease complex. AFG3L2 also interacted with itself. Loss of paraplegin in Spg7 -/- mice or in SPG7 patient fibroblasts resulted in m-AAA protease complexes made up of only homodimerized AFG7L2 that were proteolytically active against misfolded mitochondrial membrane proteins in yeast complementation assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101804" 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="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> found expression of the AFG3L2 gene in Purkinje cell bodies and dendrites of the human cerebellum and in large neurons of the deep cerebellar layer. AFG3L2 and paraplegin were also expressed in pyramidal cortical neurons and spinal motor neurons. Similar expression was found in mouse tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" 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="Konig, T., Troder, S. E., Bakka, K., Korwitz, A., Richter-Dennerlein, R., Lampe, P. A., Patron, M., Muhlmeister, M., Guerrero-Castillo, S., Brandt, U., Decker, T., Lauria, I., Paggio, A., Rizzuto, R., Rugarli, E. I., De Stefani, D., Langer, T. <strong>The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria.</strong> Molec. Cell 64: 148-162, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27642048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27642048</a>] [<a href="https://doi.org/10.1016/j.molcel.2016.08.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27642048">Konig et al. (2016)</a> found that mouse Maip1 (<a href="/entry/617267">617267</a>) interacted with the m-AAA protease subunit Afg3l2 and comigrated with Afg3l1 (<a href="/entry/603020">603020</a>), Afg3l2, and Spg7 in an approximately 2.3-MDa complex. Knockout of AFG3L2, SPG7, or MAIP1 in HeLa cells significantly reduced levels of the precursor form of EMRE (SMDT1; <a href="/entry/615588">615588</a>), an essential subunit of the mitochondrial calcium uniporter (MCU; <a href="/entry/614197">614197</a>) complex. MAIP1 interacted directly with EMRE and appeared to protect the unassembled EMRE precursor from proteolytic degradation by YME1L1 (<a href="/entry/607472">607472</a>). In contrast, the m-AAA protease degraded unassembled EMRE in an MAIP1-independent manner and thus modulated formation of the approximately 400-kD MCU complexes. Loss of m-AAA protease activity disturbed neuronal MCU assembly in mouse neuronal mitochondria, deregulated mitochondrial Ca(2+) flux in HeLa cells, and rendered embryonic mouse neurons sensitive to mitochondrial permeability transition pore opening and MCU-dependent Ca(2+)-induced cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27642048" 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 Afg3l2-null murine cells, <a href="#1" class="mim-tip-reference" title="Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F. <strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong> Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32600459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32600459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32600459[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/10.1186/s40478-020-00975-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32600459">Baderna et al. (2020)</a> found that OPA1 was processed by OMA1 at a higher rate compared to wildtype, leading to a reduction in the long isoform of OPA1 (L-OPA1), which inhibited mitochondrial fusion and triggered mitochondrial network fragmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32600459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Spinocerebellar Ataxia 28, Autosomal Dominant</em></strong></p><p>
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In affected members of 5 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified 5 different heterozygous mutations in the AFG3L2 gene (<a href="#0001">604581.0001</a>-<a href="#0005">604581.0005</a>). Studies in yeast showed that the mutations affected respiratory and proteolytic functions of the protein by both dominant-negative (E691K; <a href="#0001">604581.0001</a>), and loss-of-function (see, e.g., S674L, <a href="#0002">604581.0002</a>) mechanisms. <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> hypothesized that AFG3L2 or specific substrates of AFG3L2 may have an essential function in protecting the cerebellum from neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. <strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong> Hum. Mutat. 31: 1117-1124, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>] [<a href="https://doi.org/10.1002/humu.21342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20725928">Cagnoli et al. (2010)</a> identified 6 different missense mutations in exons 15 and 16 of the AFG3L2 gene (see, e.g., <a href="#0006">604581.0006</a>-<a href="#0009">604581.0009</a>) in 9 (2.6%) of 366 Caucasian European probands with autosomal dominant SCA who were negative for the most common triplet expansions in other genes. All mutations affected the highly conserved C-terminal peptidase-M41 domain and were predicted to destabilize the AFG3L2 complex. Pathogenic copy number variations affecting the AFG3L2 gene were not detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Spastic Ataxia 5, Autosomal Recessive</em></strong></p><p>
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By whole-exome sequencing of 2 brothers with early-onset spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>), <a href="#14" class="mim-tip-reference" title="Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others. <strong>Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.</strong> PLoS Genet. 7: e1002325, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22022284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22022284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22022284[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/10.1371/journal.pgen.1002325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22022284">Pierson et al. (2011)</a> identified a homozygous mutation in the AFG3L2 gene (Y616C; <a href="#0010">604581.0010</a>). The phenotype was characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (<a href="/entry/607259">607259</a>) phenotype with some features of a mitochondrial disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22022284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated Italian patients with a variant of SPAX5 presenting as severe progressive myoclonus and ataxia, <a href="#13" class="mim-tip-reference" title="Muona, M., Berkovic, S. F., Dibbens, L. M., Oliver, K. L., Maljevic, S., Bayly, M. A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S. E., and 39 others. <strong>A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.</strong> Nature Genet. 47: 39-46, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25401298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25401298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25401298[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25401298">Muona et al. (2015)</a> identified a homozygous missense mutation in the AFG3L2 gene (M625I; <a href="#0011">604581.0011</a>). Functional studies of the variant were not performed. The patients were ascertained from a cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25401298" 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 36-year-old woman (family 6) with SPAX5 and optic atrophy, <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified compound heterozygous missense mutations in the AFG3L2 gene (A462V, <a href="#0014">604581.0014</a> and Q620K, <a href="#0015">604581.0015</a>). The mother and brother of this patient, who were heterozygous for the A462V mutation, had optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>). The mutations were found by next-generation sequencing and confirmed by Sanger sequencing. The father of the proband was heterozygous for the Q620K variant; at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in abnormal OPA1 processing and mitochondrial fragmentation, consistent with a loss of function. The Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 18-year-old man, born of unrelated parents (family 11), with SPAX5, <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified compound heterozygous mutations in the AFG3L2 gene (<a href="#0018">604581.0018</a> and <a href="#0019">604581.0019</a>). The mutations, which were found by next-generation sequencing, segregated with the disorder in the family. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected. Functional studies of these variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 8-year-old girl (patient 2) with SPAX5, <a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a> identified compound heterozygous mutations in the AFG3L2 gene (M625I, <a href="#0011">604581.0011</a>; c.245dup, <a href="#0020">604581.0020</a>). Fibroblasts from the patient showed reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. Activation of OMA1 was detected in patient cells, evidenced by reduced OMA and OPA1 protein content. To test if the OMA1-mediated integrated stress response (ISR) was mediated through DELE1, DELE1 was silenced in patient fibroblasts, which resulted in slowed growth and reduced phosphorylation of eIF2-alpha compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37804316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Optic Atrophy 12, Autosomal Dominant</em></strong></p><p>
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In a father and son with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#6" class="mim-tip-reference" title="Charif, M., Roubertie, A., Salime, S., Mamouni, S., Goizet, C., Hamel, C. P., Lenaers, G. <strong>A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.</strong> Front. Genet. 6: 311, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539208[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/10.3389/fgene.2015.00311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539208">Charif et al. (2015)</a> identified a heterozygous missense mutation in the AFG3L2 gene (R468C; <a href="#0012">604581.0012</a>). The variant occurred at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26539208" 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 19-year-old Italian man with OPA12, <a href="#7" class="mim-tip-reference" title="Colavito, D., Maritan, V., Suppiej, A., Del Giudice, E., Mazzarolo, M., Miotto, S., Farina, S., Dalle Carbonare, L., Piermarocchi, S., Leon, A. <strong>Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.</strong> Biomed. Rep. 7: 451-454, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29181157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29181157</a>] [<a href="https://doi.org/10.3892/br.2017.987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29181157">Colavito et al. (2017)</a> identified a heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29181157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 affected individuals spanning 3 generations of a family with OPA12, <a href="#1" class="mim-tip-reference" title="Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F. <strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong> Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32600459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32600459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32600459[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/10.1186/s40478-020-00975-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32600459">Baderna et al. (2020)</a> identified a heterozygous missense variant affecting a conserved residue close to the AAA domain in the AFG3L2 gene (G337E; <a href="#0013">604581.0013</a>). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the G337E mutation abolished AFG3L2 activity, resulting in a reduction of L-OPA1 and an accumulation of S-OPA1 associated with hyperactivation of OMA1. These abnormalities were associated with altered mitochondrial morphology and dynamics and increased mitochondrial fragmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32600459" 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 affected individuals from 10 unrelated families with OPA12, <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified heterozygous missense mutations in the AFG3L2 gene (see, e.g., <a href="#0014">604581.0014</a>; <a href="#0016">604581.0016</a>-<a href="#0017">604581.0017</a>). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The variants were inherited in an autosomal dominant pattern in most families, but occurred de novo in at least 2 patients. Most of the mutations localized to the ATPase domain, which is in contrast to SCA28 or SPAX5 mutations, which tend to affect the proteolytic domain. Functional studies were performed on several of the mutations. Expression of the mutations into yeast lacking the AFG3L2 orthologs showed that the mutant proteins were unable to rescue the defective oxidative phosphorylation (OXPHOS) phenotype. The mutations also impaired proteolytic and dislocase activity of the AFG3L2-associated mAAA complex, consistent with a loss of function. Patient fibroblasts showed decreased levels of L-OPA1 compared to S-OPA1, suggesting increased proteolytic cleavage of long OPA1 and abnormal accumulation of short OPA1. This was associated with increased mitochondrial fragmentation, although OXPHOS complex activity was normal in patient cells. The findings suggested that unbalanced processing of OPA1 due to AFG3L2 dysfunction causes defective mitochondrial dynamics, resulting in optic atrophy. The authors noted that this mechanism fits with the paradigm of the pathogenic mechanism for mitochondrial optic neuropathies, in which retinal ganglion cells are vulnerable to mitochondrial dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Martinelli, P., La Mattina, V., Bernacchia, A., Magnoni, R., Cerri, F., Cox, G., Quattrini, A., Casari, G., Rugarli, E. I. <strong>Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.</strong> Hum. Molec. Genet. 18: 2001-2013, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289403</a>] [<a href="https://doi.org/10.1093/hmg/ddp124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289403">Martinelli et al. (2009)</a> reported an early-onset severe neurologic phenotype in Spg7-null/Afg3l2 +/- double-mutant mice characterized by loss of balance, tremor, and ataxia. Double-mutant mice displayed acceleration and worsening of the axonopathy observed in Spg7-null mice. In addition, they showed prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues were prone to lose mtDNA and had unstable respiratory complexes. At late stages, neurons contained structural abnormal mitochondria defective in COX-SDH reaction. <a href="#12" class="mim-tip-reference" title="Martinelli, P., La Mattina, V., Bernacchia, A., Magnoni, R., Cerri, F., Cox, G., Quattrini, A., Casari, G., Rugarli, E. I. <strong>Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.</strong> Hum. Molec. Genet. 18: 2001-2013, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289403</a>] [<a href="https://doi.org/10.1093/hmg/ddp124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289403">Martinelli et al. (2009)</a> suggested that different neuronal populations may have variable thresholds of susceptibility to reduced levels of the m-AAA protease and that impaired mitochondrial proteolysis may be a mechanism of cerebellar degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a> identified reduced OMA1 expression in the cerebellum of Afg3l2 knockout mice (Afg3l2 -/-) compared to controls at postnatal day 14 (P14). There was evidence of activation of the mitochondrial integrated stress response (ISR), including increased phosphorylation of eIF2-alpha and increased ATF4 and FGF21 gene expression, among other genes associated with ISR. <a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a> then investigated the effects of treatment with an ISR potentiator, Sephin-1, on Afg3l2 -/- mice. Pregnant mothers were treated orally with Sephin-1 and Afg3l2 -/- pups were then treated intraperitoneally with Sephin-1 injections. The treated mutant mice had improved life span and motor performance compared to untreated mutant mice. Purkinje cells from brains from the treated mutant mice at P14 had improved mitochondrial appearance and basal ATP levels compared to untreated mutant mice. <a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a> concluded that activation of the OMA1-mediated ISR response is neuroprotective in Afg3l2 -/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37804316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>20 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604581[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151344520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344520;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=rs151344520" 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=rs151344520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 11 affected members of an Italian family with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), reported by <a href="#3" class="mim-tip-reference" title="Cagnoli, C., Mariotti, C., Taroni, F., Seri, M., Brussino, A., Michielotto, C., Grisoli, M., Di Bella, D., Migone, N., Gellera, C., Di Donato, S., Brusco, A. <strong>SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2.</strong> Brain 129: 235-242, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251216</a>] [<a href="https://doi.org/10.1093/brain/awh651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251216">Cagnoli et al. (2006)</a>, <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified a heterozygous 2071G-A transition in exon 16 of the AFG3L2 gene, resulting in a glu691-to-lys (E691K) substitution within the highly conserved proteolytic domain. One asymptomatic individual carried the mutation, which was not found in 400 controls. Molecular modeling showed that the E691K substitution affects a residue that sits in the middle of the central pore surrounding the exit from the proteolytic chamber on the matrix side of the complex. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. Coexpression with wildtype AFG3L2 or paraplegin (<a href="/entry/602783">602783</a>) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16251216+20208537" 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">rs151344519 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344519;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=rs151344519" 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=rs151344519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a father and son with spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified a heterozygous 2-bp deletion/2-bp insertion (2021delCCinsTA) in exon 16 of the AFG3L2 gene, resulting in a ser674-to-leu (S674L) substitution in a portion of the proteolytic domain. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (<a href="/entry/602783">602783</a>) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPINOCEREBELLAR ATAXIA 28</strong>
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AFG3L2, ALA694GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151344521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344521;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=rs151344521" 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=rs151344521" 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=RCV000005806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005806</a>
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<p>In a man with spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified a heterozygous 2081C-A transversion in exon 16 of the AFG3L2 gene, resulting in an ala694-to-glu (A694E) substitution in a portion of the proteolytic domain. His deceased father was also affected. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (<a href="/entry/602783">602783</a>) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 SPINOCEREBELLAR ATAXIA 28</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs151344523 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344523;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/rs151344523?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=rs151344523" 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=rs151344523" 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=RCV000005807 OR RCV000487661" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005807, RCV000487661" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005807...</a>
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<p>In a 40-year-old woman with spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified a heterozygous 2105G-A transition in exon 16 of the AFG3L2 gene, resulting in an arg702-to-gln (R702Q) substitution in a portion of the proteolytic domain. The patient had onset at age 28 years of progressive gait and limb ataxia, with later development of dysarthria, ophthalmoplegia, and pyramidal signs. Brain MRI showed marked cerebellar atrophy. Two clinically unaffected family members in their seventies also carried the mutation; they both reported a subjective sense of unsteadiness and showed moderate cerebellar atrophy on brain MRI. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (<a href="/entry/602783">602783</a>) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" 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">rs151344512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344512;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=rs151344512" 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=rs151344512" 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=RCV000005808" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005808" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005808</a>
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<p>In 6 affected members of a family with spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#8" class="mim-tip-reference" title="Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. <strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong> Nature Genet. 42: 313-321, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>] [<a href="https://doi.org/10.1038/ng.544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20208537">Di Bella et al. (2010)</a> identified a heterozygous 1296A-C transversion in exon 10 of the AFG3L2 gene, resulting in an asn432-to-thr (N432T) substitution within a highly conserved region of the ATPase domain. Molecular modeling showed that the N432T substitution occurs in a conserved residue in the central pore region on the membrane side of the channel through which substrates are translocated into the proteolytic chamber. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect at high temperatures. Coexpression with wildtype AFG3L2 or paraplegin (<a href="/entry/602783">602783</a>) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 SPINOCEREBELLAR ATAXIA 28</strong>
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AFG3L2, MET666VAL
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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> rs151344514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344514;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/rs151344514?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=rs151344514" 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=rs151344514" 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=RCV000023376 OR RCV000992830 OR RCV002490407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023376, RCV000992830, RCV002490407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023376...</a>
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<p>In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#4" class="mim-tip-reference" title="Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. <strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong> Hum. Mutat. 31: 1117-1124, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>] [<a href="https://doi.org/10.1002/humu.21342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20725928">Cagnoli et al. (2010)</a> identified a heterozygous 1996A-G transition in exon 16 of the AFG3L2 gene, resulting in a met666-to-val (M666V) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" 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 SPINOCEREBELLAR ATAXIA 28</strong>
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AFG3L2, MET666ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151344515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344515;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=rs151344515" 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=rs151344515" 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=RCV000023377" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023377" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023377</a>
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<p>In 2 affected members a family with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#4" class="mim-tip-reference" title="Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. <strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong> Hum. Mutat. 31: 1117-1124, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>] [<a href="https://doi.org/10.1002/humu.21342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20725928">Cagnoli et al. (2010)</a> identified a heterozygous 1997T-G transversion in exon 16 of the AFG3L2 gene, resulting in a met666-to-arg (M666R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Met666 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" 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>.0008 SPINOCEREBELLAR ATAXIA 28</strong>
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AFG3L2, GLY671ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151344517 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344517;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=rs151344517" 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=rs151344517" 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=RCV000023378" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023378" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023378</a>
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<p>In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#4" class="mim-tip-reference" title="Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. <strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong> Hum. Mutat. 31: 1117-1124, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>] [<a href="https://doi.org/10.1002/humu.21342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20725928">Cagnoli et al. (2010)</a> identified a heterozygous 2011G-A transition in exon 16 of the AFG3L2 gene, resulting in a gly671-to-arg (G671R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. Gly671 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" 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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<span class="mim-font">
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<strong>.0009 SPINOCEREBELLAR ATAXIA 28</strong>
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AFG3L2, THR654ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs151344513 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344513;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=rs151344513" 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=rs151344513" 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=RCV000031941 OR RCV004719667" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031941, RCV004719667" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031941...</a>
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<p>In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; <a href="/entry/610246">610246</a>), <a href="#4" class="mim-tip-reference" title="Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. <strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong> Hum. Mutat. 31: 1117-1124, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>] [<a href="https://doi.org/10.1002/humu.21342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20725928">Cagnoli et al. (2010)</a> identified a heterozygous 1961C-T transition in exon 15 of the AFG3L2 gene, resulting in a thr654-to-ile (T654I) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" 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> rs387906889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906889;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/rs387906889?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=rs387906889" 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=rs387906889" 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=RCV000023380 OR RCV000414375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023380, RCV000414375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023380...</a>
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<p>In 2 brothers, born of consanguineous Hispanic parents from Colombia, with autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>), <a href="#14" class="mim-tip-reference" title="Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others. <strong>Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.</strong> PLoS Genet. 7: e1002325, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22022284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22022284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22022284[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/10.1371/journal.pgen.1002325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22022284">Pierson et al. (2011)</a> identified a homozygous 1847G-A transition in the AFG3L2 gene, resulting in a tyr616-to-cys (Y616C) substitution in a highly conserved residue at the beginning of the proteolytic domain. The mutation was found by whole-exome sequencing. The older patient developed spastic gait at age 2 years and eventually lost the ability to ambulate independently, whereas the younger brother never acquired independent ambulation and died at age 13 years of pneumonia. Both developed progressive myoclonic epilepsy associated with generalized tonic-clonic seizures at age 8 years. This was followed by progressive dysarthria, dysphagia, motor degeneration, and lower extremity weakness with distal muscle atrophy. The older brother showed dysmetria, dysdiadochokinesia, ataxic dysarthria, ptosis, oculomotor apraxia, and dystonic movements. Cognition was normal. Brain MRI showed moderate cerebellar atrophy, and nerve conduction studies showed an axonal sensorimotor neuropathy of the lower extremities. Electron microscopy of skeletal muscle showed misplaced mitochondria associated with large lipid droplets, and there was decreased mtDNA copy number. Both parents were without neurologic complaints and had normal neurologic and ophthalmologic exams, although the mother had mild cerebellar atrophy on brain imaging. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin (SPG7; <a href="/entry/602783">602783</a>) in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (<a href="/entry/607259">607259</a>) phenotype with some features of a mitochondrial disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22022284" 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> rs727502823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727502823;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/rs727502823?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=rs727502823" 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=rs727502823" 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=RCV000149914 OR RCV002265626 OR RCV003144139" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149914, RCV002265626, RCV003144139" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149914...</a>
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<p>In 2 unrelated Italian patients with a variant of autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>), presenting as severe progressive myoclonus and ataxia, <a href="#13" class="mim-tip-reference" title="Muona, M., Berkovic, S. F., Dibbens, L. M., Oliver, K. L., Maljevic, S., Bayly, M. A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S. E., and 39 others. <strong>A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.</strong> Nature Genet. 47: 39-46, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25401298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25401298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25401298[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25401298">Muona et al. (2015)</a> identified a homozygous c.1875G-A transition in the AFG3L2 gene, resulting in a met625-to-ile (M625I) substitution at a conserved residue in the proteolytic domain. The mutation, which was found by exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant were not performed. Haplotype analysis suggested that the mutation was identical by descent, although the patients were not known to be related. The patients were ascertained from a larger cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25401298" 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 girl (patient 2) with SPAX5, <a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a> identified compound heterozygous mutations in the AFG3L2 gene: M625I and a 1-bp duplication (c.245dup; <a href="#0020">604581.0020</a>) predicted to result in a frameshift and premature termination (Asn82LysfsTer6). The mutations were identified by sequencing of a panel of nuclear genes associated with mitochondrial disease. Each parent was a carrier of one of the mutations. Fibroblasts from the patient demonstrated reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37804316" 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">rs1020764190 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1020764190;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=rs1020764190" 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=rs1020764190" 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=RCV000684752 OR RCV001253809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000684752, RCV001253809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000684752...</a>
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<p>In a father and son with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#6" class="mim-tip-reference" title="Charif, M., Roubertie, A., Salime, S., Mamouni, S., Goizet, C., Hamel, C. P., Lenaers, G. <strong>A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.</strong> Front. Genet. 6: 311, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539208[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/10.3389/fgene.2015.00311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539208">Charif et al. (2015)</a> identified a heterozygous c.1402C-T transition in exon 11 of the AFG3L2 gene, resulting in an arg468-to-cys (R468C) substitution at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26539208" 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 19-year-old Italian man with OPA12, <a href="#7" class="mim-tip-reference" title="Colavito, D., Maritan, V., Suppiej, A., Del Giudice, E., Mazzarolo, M., Miotto, S., Farina, S., Dalle Carbonare, L., Piermarocchi, S., Leon, A. <strong>Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.</strong> Biomed. Rep. 7: 451-454, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29181157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29181157</a>] [<a href="https://doi.org/10.3892/br.2017.987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29181157">Colavito et al. (2017)</a> identified heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29181157" 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">rs1908566777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1908566777;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=rs1908566777" 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=rs1908566777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 affected individuals spanning 3 generations of a family with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#1" class="mim-tip-reference" title="Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F. <strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong> Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32600459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32600459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32600459[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/10.1186/s40478-020-00975-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32600459">Baderna et al. (2020)</a> identified a heterozygous c.1010G-A transition (c.1010G-A, NM_006796.2) in exon 8 of the AFG3L2 gene, resulting in a gly337-to-glu (G337E) substitution at a conserved residue close to the AAA domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. Overexpression of G337E, unlike expression of wildtype AFG3L2, failed to rescue mitochondrial fragmentation defects in Afg3l2-null murine cells, indicating that the G337E mutation abolishes AFG3L2 activity. Patient fibroblasts showed abnormal mitochondrial morphology with increased fragmentation of the mitochondrial network, a reduction of L-OPA1 (<a href="/entry/605290">605290</a>), and an accumulation of S-OPA1 associated with hyperactivation of OMA1 (<a href="/entry/617081">617081</a>). The findings were consistent with a defect in mitochondrial dynamics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32600459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 OPTIC ATROPHY 12</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">rs912546325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs912546325;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=rs912546325" 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=rs912546325" 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=RCV000658802 OR RCV001249473 OR RCV001249477 OR RCV001253811 OR RCV001253812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000658802, RCV001249473, RCV001249477, RCV001253811, RCV001253812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000658802...</a>
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<p>In affected members of 2 unrelated multigenerational families (F1 and F2) with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified a heterozygous c.1385C-T transition (c.1385C-T, NM_006796.3) in the AFG3L2 gene, resulting in an ala462-to-val (A462V) substitution in the ATPase domain. A mother and son from another family (F6) with OPA12 were heterozygous for the A462V mutation; the 65-year-old mother also had cervical dystonia. Her daughter was compound heterozygous for A462V and a c.1858C-A transversion, resulting in a gln620-to-lys (Q620K; <a href="#0015">604581.0015</a>) substitution in the proteolytic domain. She had a more severe phenotype, consistent with autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>). The father of this patient was heterozygous for the Q620K variant: at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in a loss of function and caused mitochondrial fragmentation. Of note, the Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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">rs1907907851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1907907851;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=rs1907907851" 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=rs1907907851" 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=RCV001249477 OR RCV001253808" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249477, RCV001253808" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249477...</a>
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<p>For discussion of the c.1858C-A transversion (c.1858C-A, NM_006796.3) in the AFG3L2 gene, resulting in a gln620-to-lys (Q620K) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>) by <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a>, see <a href="#0014">604581.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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">rs1908371616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1908371616;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=rs1908371616" 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=rs1908371616" 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=RCV001249475 OR RCV001253813 OR RCV005057154" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249475, RCV001253813, RCV005057154" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249475...</a>
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<p>In a father and son (family 4) with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified a heterozygous c.1220A-G transition (c.1220A-G, NM_006796.3) in the AFG3L2 gene, resulting in an asp407-to-gly (D407G) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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">rs1908300748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1908300748;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=rs1908300748" 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=rs1908300748" 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=RCV001249476 OR RCV001253814" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249476, RCV001253814" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249476...</a>
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<p>In a father and son (family 5) with optic atrophy-12 (OPA12; <a href="/entry/618977">618977</a>), <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified a heterozygous c.1541C-T transition (c.1541C-T, NM_006796.3) in the AFG3L2 gene, resulting in a pro514-to-leu (P514L) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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>.0018 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1907906060 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1907906060;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=rs1907906060" 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=rs1907906060" 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=RCV001249482 OR RCV001253815" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249482, RCV001253815" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249482...</a>
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<p>In an 18-year-old man, born of unrelated parents (family 11), with autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>), <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a> identified compound heterozygous mutations in the AFG3L2 gene: a 2-bp deletion (c.1901_1902delCT, NM_006796.3), resulting in a frameshift and premature termination (Ser634Ter), and a c.916A-G transition, resulting in a lys306-to-glu (K306E; <a href="#0019">604581.0019</a>) substitution. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the gnomAD database. Functional studies of the variants were not performed. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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">rs1908569446 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1908569446;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=rs1908569446" 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=rs1908569446" 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=RCV001249482 OR RCV001253816" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249482, RCV001253816" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249482...</a>
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<p>For discussion of the c.916A-G transition (c.916A-G, NM_006796.3) in the AFG3L2 gene, resulting in a lys306-to-glu (K306E) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>) by <a href="#5" class="mim-tip-reference" title="Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. <strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong> Ann. Neurol. 88: 18-32, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32219868">Caporali et al. (2020)</a>, see <a href="#0018">604581.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32219868" 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>.0020 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004595412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004595412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004595412</a>
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<p>For discussion of the 1-bp duplication (c.245dup) in the AFG3L2 gene, predicted to result in a frameshift and premature termination (Asn82LysfsTer6), that was identified in compound heterozygous state in a girl (patient 2) with spastic ataxia-5 (SPAX5; <a href="/entry/614487">614487</a>) by <a href="#9" class="mim-tip-reference" title="Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. <strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong> Brain 147: 1043-1056, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37804316">Franchino et al. (2024)</a>, see <a href="#0011">604581.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37804316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F.
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<strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong>
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Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32600459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32600459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32600459[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=32600459" 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/10.1186/s40478-020-00975-w" target="_blank">Full Text</a>]
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Banfi, S, Bassi, M. T., Andolfi, G., Marchitiello, A., Zanotta, S., Ballabio, A., Casari, G., Franco, B.
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<strong>Identification and characterization of AFG3L2, a novel paraplegin-related gene.</strong>
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Genomics 59: 51-58, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395799</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10395799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1999.5818" target="_blank">Full Text</a>]
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Cagnoli, C., Mariotti, C., Taroni, F., Seri, M., Brussino, A., Michielotto, C., Grisoli, M., Di Bella, D., Migone, N., Gellera, C., Di Donato, S., Brusco, A.
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<strong>SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2.</strong>
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Brain 129: 235-242, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251216</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251216" 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/awh651" target="_blank">Full Text</a>]
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Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A.
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<strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong>
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Hum. Mutat. 31: 1117-1124, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20725928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20725928</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20725928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21342" target="_blank">Full Text</a>]
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Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others.
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<strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong>
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Ann. Neurol. 88: 18-32, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32219868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32219868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32219868[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=32219868" 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.25723" target="_blank">Full Text</a>]
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Charif, M., Roubertie, A., Salime, S., Mamouni, S., Goizet, C., Hamel, C. P., Lenaers, G.
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<strong>A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.</strong>
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Front. Genet. 6: 311, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539208[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=26539208" 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/10.3389/fgene.2015.00311" target="_blank">Full Text</a>]
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Colavito, D., Maritan, V., Suppiej, A., Del Giudice, E., Mazzarolo, M., Miotto, S., Farina, S., Dalle Carbonare, L., Piermarocchi, S., Leon, A.
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<strong>Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.</strong>
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Biomed. Rep. 7: 451-454, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29181157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29181157</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29181157" 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/10.3892/br.2017.987" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Di Bella2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others.
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<strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong>
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|
Nature Genet. 42: 313-321, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20208537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20208537</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20208537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.544" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Franchino2024" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F.
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|
<strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong>
|
|
Brain 147: 1043-1056, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37804316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37804316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37804316[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=37804316" 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/awad340" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Konig2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Konig, T., Troder, S. E., Bakka, K., Korwitz, A., Richter-Dennerlein, R., Lampe, P. A., Patron, M., Muhlmeister, M., Guerrero-Castillo, S., Brandt, U., Decker, T., Lauria, I., Paggio, A., Rizzuto, R., Rugarli, E. I., De Stefani, D., Langer, T.
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|
<strong>The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria.</strong>
|
|
Molec. Cell 64: 148-162, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27642048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27642048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27642048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2016.08.020" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Koppen2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Koppen, M., Metodiev, M. D., Casari, G., Rugarli, E. I., Langer, T.
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<strong>Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia.</strong>
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Molec. Cell. Biol. 27: 758-767, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101804</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17101804[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=17101804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.01470-06" target="_blank">Full Text</a>]
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Martinelli2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Martinelli, P., La Mattina, V., Bernacchia, A., Magnoni, R., Cerri, F., Cox, G., Quattrini, A., Casari, G., Rugarli, E. I.
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<strong>Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.</strong>
|
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Hum. Molec. Genet. 18: 2001-2013, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289403</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289403" 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/ddp124" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Muona2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Muona, M., Berkovic, S. F., Dibbens, L. M., Oliver, K. L., Maljevic, S., Bayly, M. A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S. E., and 39 others.
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<strong>A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.</strong>
|
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Nature Genet. 47: 39-46, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25401298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25401298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25401298[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=25401298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.3144" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Pierson2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others.
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<strong>Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.</strong>
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PLoS Genet. 7: e1002325, 2011. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22022284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22022284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22022284[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=22022284" 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/10.1371/journal.pgen.1002325" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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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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Hilary J. Vernon - updated : 07/17/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 08/10/2020<br>Patricia A. Hartz - updated : 12/20/2016<br>Cassandra L. Kniffin - updated : 1/16/2015<br>Cassandra L. Kniffin - updated : 2/24/2011<br>Cassandra L. Kniffin - updated : 5/6/2010<br>George E. Tiller - updated : 2/24/2010<br>Patricia A. Hartz - updated : 6/2/2009
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 2/19/2000
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/17/2024
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/05/2021<br>carol : 08/17/2020<br>carol : 08/14/2020<br>carol : 08/13/2020<br>ckniffin : 08/10/2020<br>carol : 01/05/2018<br>mgross : 12/20/2016<br>carol : 01/20/2015<br>mcolton : 1/16/2015<br>ckniffin : 1/16/2015<br>terry : 4/10/2012<br>carol : 4/6/2012<br>terry : 3/2/2012<br>carol : 3/2/2012<br>ckniffin : 2/20/2012<br>wwang : 3/18/2011<br>ckniffin : 2/24/2011<br>wwang : 5/18/2010<br>ckniffin : 5/6/2010<br>ckniffin : 5/6/2010<br>wwang : 2/26/2010<br>terry : 2/24/2010<br>mgross : 6/2/2009<br>terry : 6/2/2009<br>cwells : 11/5/2003<br>carol : 2/21/2000
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</span>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604581
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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AFG3-LIKE MATRIX AAA PEPTIDASE, SUBUNIT 2; AFG3L2
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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ATPase FAMILY GENE 3-LIKE 2
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: AFG3L2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 715824008, 771469002;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 18p11.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:12,328,944-12,377,227 </span>
|
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
|
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<tbody>
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<tr>
|
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<td rowspan="3">
|
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<span class="mim-font">
|
|
18p11.21
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Optic atrophy 12
|
|
</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
618977
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Spastic ataxia 5, autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
614487
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Spinocerebellar ataxia 28
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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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610246
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>AFG3L2 is the catalytic subunit of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (summary by Koppen et al., 2007). AFG3L2 also regulates the processing of OPA1 (605290) through OMA1 (617081), which ultimately affects mitochondrial dynamics (summary by Baderna et al., 2020). </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 searching an EST database with the sequence of paraplegin (SPG7; 602783) and screening a fetal brain cDNA library, Banfi et al. (1999) identified a cDNA for AFG3L2. AFG3L2 encodes a deduced 797-amino acid protein whose sequence shows 69% similarity to the yeast Afg3 mitochondrial ATPase and 49% identity to paraplegin. AFG3L2 contains an AAA (for ATPase associated with diverse cellular activities) domain of about 190 amino acids with an ATP/GTP-binding site, a zinc-dependent binding domain, and an RNA-binding region. Northern blot analysis revealed that AFG3L2 is expressed ubiquitously as a 3.2-kb transcript in fetal and adult tissues, with greatest expression in heart and skeletal muscle. Fluorescence microscopy showed that AFG3L2 is localized in mitochondria. Thus, AFG3L2 and paraplegin share a similar expression pattern and the same localization. </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>Di Bella et al. (2010) noted that the AFG3L2 gene contains 17 exons spanning 48 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Banfi et al. (1999) mapped the AFG3L2 gene to chromosome 18p11. Di Bella et al. (2010) noted that the AFG3L2 gene maps to chromosome 18p11.21. </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>Using in vitro protein binding assays and immunoprecipitation analysis, Koppen et al. (2007) showed that paraplegin interacted with AFG3L2 in the m-AAA protease complex. AFG3L2 also interacted with itself. Loss of paraplegin in Spg7 -/- mice or in SPG7 patient fibroblasts resulted in m-AAA protease complexes made up of only homodimerized AFG7L2 that were proteolytically active against misfolded mitochondrial membrane proteins in yeast complementation assays. </p><p>Di Bella et al. (2010) found expression of the AFG3L2 gene in Purkinje cell bodies and dendrites of the human cerebellum and in large neurons of the deep cerebellar layer. AFG3L2 and paraplegin were also expressed in pyramidal cortical neurons and spinal motor neurons. Similar expression was found in mouse tissues. </p><p>Konig et al. (2016) found that mouse Maip1 (617267) interacted with the m-AAA protease subunit Afg3l2 and comigrated with Afg3l1 (603020), Afg3l2, and Spg7 in an approximately 2.3-MDa complex. Knockout of AFG3L2, SPG7, or MAIP1 in HeLa cells significantly reduced levels of the precursor form of EMRE (SMDT1; 615588), an essential subunit of the mitochondrial calcium uniporter (MCU; 614197) complex. MAIP1 interacted directly with EMRE and appeared to protect the unassembled EMRE precursor from proteolytic degradation by YME1L1 (607472). In contrast, the m-AAA protease degraded unassembled EMRE in an MAIP1-independent manner and thus modulated formation of the approximately 400-kD MCU complexes. Loss of m-AAA protease activity disturbed neuronal MCU assembly in mouse neuronal mitochondria, deregulated mitochondrial Ca(2+) flux in HeLa cells, and rendered embryonic mouse neurons sensitive to mitochondrial permeability transition pore opening and MCU-dependent Ca(2+)-induced cell death. </p><p>In Afg3l2-null murine cells, Baderna et al. (2020) found that OPA1 was processed by OMA1 at a higher rate compared to wildtype, leading to a reduction in the long isoform of OPA1 (L-OPA1), which inhibited mitochondrial fusion and triggered mitochondrial network fragmentation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Spinocerebellar Ataxia 28, Autosomal Dominant</em></strong></p><p>
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In affected members of 5 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified 5 different heterozygous mutations in the AFG3L2 gene (604581.0001-604581.0005). Studies in yeast showed that the mutations affected respiratory and proteolytic functions of the protein by both dominant-negative (E691K; 604581.0001), and loss-of-function (see, e.g., S674L, 604581.0002) mechanisms. Di Bella et al. (2010) hypothesized that AFG3L2 or specific substrates of AFG3L2 may have an essential function in protecting the cerebellum from neurodegeneration. </p><p>Cagnoli et al. (2010) identified 6 different missense mutations in exons 15 and 16 of the AFG3L2 gene (see, e.g., 604581.0006-604581.0009) in 9 (2.6%) of 366 Caucasian European probands with autosomal dominant SCA who were negative for the most common triplet expansions in other genes. All mutations affected the highly conserved C-terminal peptidase-M41 domain and were predicted to destabilize the AFG3L2 complex. Pathogenic copy number variations affecting the AFG3L2 gene were not detected. </p><p><strong><em>Spastic Ataxia 5, Autosomal Recessive</em></strong></p><p>
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By whole-exome sequencing of 2 brothers with early-onset spastic ataxia-5 (SPAX5; 614487), Pierson et al. (2011) identified a homozygous mutation in the AFG3L2 gene (Y616C; 604581.0010). The phenotype was characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder. </p><p>In 2 unrelated Italian patients with a variant of SPAX5 presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous missense mutation in the AFG3L2 gene (M625I; 604581.0011). Functional studies of the variant were not performed. The patients were ascertained from a cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing. </p><p>In a 36-year-old woman (family 6) with SPAX5 and optic atrophy, Caporali et al. (2020) identified compound heterozygous missense mutations in the AFG3L2 gene (A462V, 604581.0014 and Q620K, 604581.0015). The mother and brother of this patient, who were heterozygous for the A462V mutation, had optic atrophy-12 (OPA12; 618977). The mutations were found by next-generation sequencing and confirmed by Sanger sequencing. The father of the proband was heterozygous for the Q620K variant; at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in abnormal OPA1 processing and mitochondrial fragmentation, consistent with a loss of function. The Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation. </p><p>In an 18-year-old man, born of unrelated parents (family 11), with SPAX5, Caporali et al. (2020) identified compound heterozygous mutations in the AFG3L2 gene (604581.0018 and 604581.0019). The mutations, which were found by next-generation sequencing, segregated with the disorder in the family. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected. Functional studies of these variants were not performed. </p><p>In an 8-year-old girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene (M625I, 604581.0011; c.245dup, 604581.0020). Fibroblasts from the patient showed reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. Activation of OMA1 was detected in patient cells, evidenced by reduced OMA and OPA1 protein content. To test if the OMA1-mediated integrated stress response (ISR) was mediated through DELE1, DELE1 was silenced in patient fibroblasts, which resulted in slowed growth and reduced phosphorylation of eIF2-alpha compared to controls. </p><p><strong><em>Optic Atrophy 12, Autosomal Dominant</em></strong></p><p>
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|
In a father and son with optic atrophy-12 (OPA12; 618977), Charif et al. (2015) identified a heterozygous missense mutation in the AFG3L2 gene (R468C; 604581.0012). The variant occurred at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation. </p><p>In a 19-year-old Italian man with OPA12, Colavito et al. (2017) identified a heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability. </p><p>In 5 affected individuals spanning 3 generations of a family with OPA12, Baderna et al. (2020) identified a heterozygous missense variant affecting a conserved residue close to the AAA domain in the AFG3L2 gene (G337E; 604581.0013). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the G337E mutation abolished AFG3L2 activity, resulting in a reduction of L-OPA1 and an accumulation of S-OPA1 associated with hyperactivation of OMA1. These abnormalities were associated with altered mitochondrial morphology and dynamics and increased mitochondrial fragmentation. </p><p>In affected individuals from 10 unrelated families with OPA12, Caporali et al. (2020) identified heterozygous missense mutations in the AFG3L2 gene (see, e.g., 604581.0014; 604581.0016-604581.0017). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The variants were inherited in an autosomal dominant pattern in most families, but occurred de novo in at least 2 patients. Most of the mutations localized to the ATPase domain, which is in contrast to SCA28 or SPAX5 mutations, which tend to affect the proteolytic domain. Functional studies were performed on several of the mutations. Expression of the mutations into yeast lacking the AFG3L2 orthologs showed that the mutant proteins were unable to rescue the defective oxidative phosphorylation (OXPHOS) phenotype. The mutations also impaired proteolytic and dislocase activity of the AFG3L2-associated mAAA complex, consistent with a loss of function. Patient fibroblasts showed decreased levels of L-OPA1 compared to S-OPA1, suggesting increased proteolytic cleavage of long OPA1 and abnormal accumulation of short OPA1. This was associated with increased mitochondrial fragmentation, although OXPHOS complex activity was normal in patient cells. The findings suggested that unbalanced processing of OPA1 due to AFG3L2 dysfunction causes defective mitochondrial dynamics, resulting in optic atrophy. The authors noted that this mechanism fits with the paradigm of the pathogenic mechanism for mitochondrial optic neuropathies, in which retinal ganglion cells are vulnerable to mitochondrial dysfunction. </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>Martinelli et al. (2009) reported an early-onset severe neurologic phenotype in Spg7-null/Afg3l2 +/- double-mutant mice characterized by loss of balance, tremor, and ataxia. Double-mutant mice displayed acceleration and worsening of the axonopathy observed in Spg7-null mice. In addition, they showed prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues were prone to lose mtDNA and had unstable respiratory complexes. At late stages, neurons contained structural abnormal mitochondria defective in COX-SDH reaction. Martinelli et al. (2009) suggested that different neuronal populations may have variable thresholds of susceptibility to reduced levels of the m-AAA protease and that impaired mitochondrial proteolysis may be a mechanism of cerebellar degeneration. </p><p>Franchino et al. (2024) identified reduced OMA1 expression in the cerebellum of Afg3l2 knockout mice (Afg3l2 -/-) compared to controls at postnatal day 14 (P14). There was evidence of activation of the mitochondrial integrated stress response (ISR), including increased phosphorylation of eIF2-alpha and increased ATF4 and FGF21 gene expression, among other genes associated with ISR. Franchino et al. (2024) then investigated the effects of treatment with an ISR potentiator, Sephin-1, on Afg3l2 -/- mice. Pregnant mothers were treated orally with Sephin-1 and Afg3l2 -/- pups were then treated intraperitoneally with Sephin-1 injections. The treated mutant mice had improved life span and motor performance compared to untreated mutant mice. Purkinje cells from brains from the treated mutant mice at P14 had improved mitochondrial appearance and basal ATP levels compared to untreated mutant mice. Franchino et al. (2024) concluded that activation of the OMA1-mediated ISR response is neuroprotective in Afg3l2 -/- mice. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>20 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 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, GLU691LYS
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<br />
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SNP: rs151344520,
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ClinVar: RCV000005804
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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 11 affected members of an Italian family with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), reported by Cagnoli et al. (2006), Di Bella et al. (2010) identified a heterozygous 2071G-A transition in exon 16 of the AFG3L2 gene, resulting in a glu691-to-lys (E691K) substitution within the highly conserved proteolytic domain. One asymptomatic individual carried the mutation, which was not found in 400 controls. Molecular modeling showed that the E691K substitution affects a residue that sits in the middle of the central pore surrounding the exit from the proteolytic chamber on the matrix side of the complex. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. Coexpression with wildtype AFG3L2 or paraplegin (602783) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, 2-BP DEL/2-BP INS, NT2021
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<br />
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SNP: rs151344519,
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ClinVar: RCV000005805
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and son with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2-bp deletion/2-bp insertion (2021delCCinsTA) in exon 16 of the AFG3L2 gene, resulting in a ser674-to-leu (S674L) substitution in a portion of the proteolytic domain. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, ALA694GLU
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<br />
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SNP: rs151344521,
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ClinVar: RCV000005806
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a man with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2081C-A transversion in exon 16 of the AFG3L2 gene, resulting in an ala694-to-glu (A694E) substitution in a portion of the proteolytic domain. His deceased father was also affected. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, ARG702GLN
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<br />
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SNP: rs151344523,
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gnomAD: rs151344523,
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ClinVar: RCV000005807, RCV000487661
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 40-year-old woman with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2105G-A transition in exon 16 of the AFG3L2 gene, resulting in an arg702-to-gln (R702Q) substitution in a portion of the proteolytic domain. The patient had onset at age 28 years of progressive gait and limb ataxia, with later development of dysarthria, ophthalmoplegia, and pyramidal signs. Brain MRI showed marked cerebellar atrophy. Two clinically unaffected family members in their seventies also carried the mutation; they both reported a subjective sense of unsteadiness and showed moderate cerebellar atrophy on brain MRI. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>.0005 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, ASN432THR
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<br />
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SNP: rs151344512,
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ClinVar: RCV000005808
|
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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 6 affected members of a family with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 1296A-C transversion in exon 10 of the AFG3L2 gene, resulting in an asn432-to-thr (N432T) substitution within a highly conserved region of the ATPase domain. Molecular modeling showed that the N432T substitution occurs in a conserved residue in the central pore region on the membrane side of the channel through which substrates are translocated into the proteolytic chamber. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect at high temperatures. Coexpression with wildtype AFG3L2 or paraplegin (602783) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 SPINOCEREBELLAR ATAXIA 28</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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AFG3L2, MET666VAL
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<br />
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SNP: rs151344514,
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gnomAD: rs151344514,
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ClinVar: RCV000023376, RCV000992830, RCV002490407
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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 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1996A-G transition in exon 16 of the AFG3L2 gene, resulting in a met666-to-val (M666V) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 SPINOCEREBELLAR ATAXIA 28</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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AFG3L2, MET666ARG
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<br />
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SNP: rs151344515,
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ClinVar: RCV000023377
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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 affected members a family with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1997T-G transversion in exon 16 of the AFG3L2 gene, resulting in a met666-to-arg (M666R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Met666 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 SPINOCEREBELLAR ATAXIA 28</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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AFG3L2, GLY671ARG
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<br />
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SNP: rs151344517,
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ClinVar: RCV000023378
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 2011G-A transition in exon 16 of the AFG3L2 gene, resulting in a gly671-to-arg (G671R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. Gly671 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPINOCEREBELLAR ATAXIA 28</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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AFG3L2, THR654ILE
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<br />
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SNP: rs151344513,
|
|
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|
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ClinVar: RCV000031941, RCV004719667
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1961C-T transition in exon 15 of the AFG3L2 gene, resulting in a thr654-to-ile (T654I) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, TYR616CYS
|
|
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|
|
|
<br />
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|
|
SNP: rs387906889,
|
|
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|
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gnomAD: rs387906889,
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|
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ClinVar: RCV000023380, RCV000414375
|
|
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|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers, born of consanguineous Hispanic parents from Colombia, with autosomal recessive spastic ataxia-5 (SPAX5; 614487), Pierson et al. (2011) identified a homozygous 1847G-A transition in the AFG3L2 gene, resulting in a tyr616-to-cys (Y616C) substitution in a highly conserved residue at the beginning of the proteolytic domain. The mutation was found by whole-exome sequencing. The older patient developed spastic gait at age 2 years and eventually lost the ability to ambulate independently, whereas the younger brother never acquired independent ambulation and died at age 13 years of pneumonia. Both developed progressive myoclonic epilepsy associated with generalized tonic-clonic seizures at age 8 years. This was followed by progressive dysarthria, dysphagia, motor degeneration, and lower extremity weakness with distal muscle atrophy. The older brother showed dysmetria, dysdiadochokinesia, ataxic dysarthria, ptosis, oculomotor apraxia, and dystonic movements. Cognition was normal. Brain MRI showed moderate cerebellar atrophy, and nerve conduction studies showed an axonal sensorimotor neuropathy of the lower extremities. Electron microscopy of skeletal muscle showed misplaced mitochondria associated with large lipid droplets, and there was decreased mtDNA copy number. Both parents were without neurologic complaints and had normal neurologic and ophthalmologic exams, although the mother had mild cerebellar atrophy on brain imaging. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin (SPG7; 602783) in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, MET625ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs727502823,
|
|
|
|
|
|
gnomAD: rs727502823,
|
|
|
|
|
|
ClinVar: RCV000149914, RCV002265626, RCV003144139
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated Italian patients with a variant of autosomal recessive spastic ataxia-5 (SPAX5; 614487), presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous c.1875G-A transition in the AFG3L2 gene, resulting in a met625-to-ile (M625I) substitution at a conserved residue in the proteolytic domain. The mutation, which was found by exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant were not performed. Haplotype analysis suggested that the mutation was identical by descent, although the patients were not known to be related. The patients were ascertained from a larger cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing. </p><p>In a girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene: M625I and a 1-bp duplication (c.245dup; 604581.0020) predicted to result in a frameshift and premature termination (Asn82LysfsTer6). The mutations were identified by sequencing of a panel of nuclear genes associated with mitochondrial disease. Each parent was a carrier of one of the mutations. Fibroblasts from the patient demonstrated reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 OPTIC ATROPHY 12</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, ARG468CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1020764190,
|
|
|
|
|
|
|
|
ClinVar: RCV000684752, RCV001253809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son with optic atrophy-12 (OPA12; 618977), Charif et al. (2015) identified a heterozygous c.1402C-T transition in exon 11 of the AFG3L2 gene, resulting in an arg468-to-cys (R468C) substitution at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation. </p><p>In a 19-year-old Italian man with OPA12, Colavito et al. (2017) identified heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability. </p>
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
|
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 OPTIC ATROPHY 12</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, GLY337GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1908566777,
|
|
|
|
|
|
|
|
ClinVar: RCV001253810
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected individuals spanning 3 generations of a family with optic atrophy-12 (OPA12; 618977), Baderna et al. (2020) identified a heterozygous c.1010G-A transition (c.1010G-A, NM_006796.2) in exon 8 of the AFG3L2 gene, resulting in a gly337-to-glu (G337E) substitution at a conserved residue close to the AAA domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. Overexpression of G337E, unlike expression of wildtype AFG3L2, failed to rescue mitochondrial fragmentation defects in Afg3l2-null murine cells, indicating that the G337E mutation abolishes AFG3L2 activity. Patient fibroblasts showed abnormal mitochondrial morphology with increased fragmentation of the mitochondrial network, a reduction of L-OPA1 (605290), and an accumulation of S-OPA1 associated with hyperactivation of OMA1 (617081). The findings were consistent with a defect in mitochondrial dynamics. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 OPTIC ATROPHY 12</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, ALA462VAL
|
|
|
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|
<br />
|
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|
|
SNP: rs912546325,
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|
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|
|
ClinVar: RCV000658802, RCV001249473, RCV001249477, RCV001253811, RCV001253812
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated multigenerational families (F1 and F2) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1385C-T transition (c.1385C-T, NM_006796.3) in the AFG3L2 gene, resulting in an ala462-to-val (A462V) substitution in the ATPase domain. A mother and son from another family (F6) with OPA12 were heterozygous for the A462V mutation; the 65-year-old mother also had cervical dystonia. Her daughter was compound heterozygous for A462V and a c.1858C-A transversion, resulting in a gln620-to-lys (Q620K; 604581.0015) substitution in the proteolytic domain. She had a more severe phenotype, consistent with autosomal recessive spastic ataxia-5 (SPAX5; 614487). The father of this patient was heterozygous for the Q620K variant: at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in a loss of function and caused mitochondrial fragmentation. Of note, the Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
AFG3L2, GLN620LYS
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|
|
<br />
|
|
|
|
SNP: rs1907907851,
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|
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|
|
ClinVar: RCV001249477, RCV001253808
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1858C-A transversion (c.1858C-A, NM_006796.3) in the AFG3L2 gene, resulting in a gln620-to-lys (Q620K) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; 614487) by Caporali et al. (2020), see 604581.0014. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 OPTIC ATROPHY 12</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AFG3L2, ASP407GLY
|
|
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|
<br />
|
|
|
|
SNP: rs1908371616,
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|
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|
|
ClinVar: RCV001249475, RCV001253813, RCV005057154
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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<p>In a father and son (family 4) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1220A-G transition (c.1220A-G, NM_006796.3) in the AFG3L2 gene, resulting in an asp407-to-gly (D407G) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 OPTIC ATROPHY 12</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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AFG3L2, PRO514LEU
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<br />
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SNP: rs1908300748,
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ClinVar: RCV001249476, RCV001253814
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and son (family 5) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1541C-T transition (c.1541C-T, NM_006796.3) in the AFG3L2 gene, resulting in a pro514-to-leu (P514L) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation. </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">
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<strong>.0018 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AFG3L2, 2-BP DEL, 1901CT
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<br />
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SNP: rs1907906060,
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ClinVar: RCV001249482, RCV001253815
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 18-year-old man, born of unrelated parents (family 11), with autosomal recessive spastic ataxia-5 (SPAX5; 614487), Caporali et al. (2020) identified compound heterozygous mutations in the AFG3L2 gene: a 2-bp deletion (c.1901_1902delCT, NM_006796.3), resulting in a frameshift and premature termination (Ser634Ter), and a c.916A-G transition, resulting in a lys306-to-glu (K306E; 604581.0019) substitution. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the gnomAD database. Functional studies of the variants were not performed. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected. </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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<h4>
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<span class="mim-font">
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<strong>.0019 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AFG3L2, LYS306GLU
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<br />
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SNP: rs1908569446,
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ClinVar: RCV001249482, RCV001253816
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.916A-G transition (c.916A-G, NM_006796.3) in the AFG3L2 gene, resulting in a lys306-to-glu (K306E) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; 614487) by Caporali et al. (2020), see 604581.0018. </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>.0020 SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AFG3L2, 1-BP DUP, NT45
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<br />
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ClinVar: RCV004595412
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp duplication (c.245dup) in the AFG3L2 gene, predicted to result in a frameshift and premature termination (Asn82LysfsTer6), that was identified in compound heterozygous state in a girl (patient 2) with spastic ataxia-5 (SPAX5; 614487) by Franchino et al. (2024), see 604581.0011. </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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Baderna, V., Schultz, J., Kearns, L. S., Fahey, M., Thompson, B. A., Ruddle, J. B., Huq, A., Maltecca, F.
|
|
<strong>A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.</strong>
|
|
Acta Neuropath. Commun. 8: 93, 2020. Note: Electronic Article.
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[PubMed: 32600459]
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[Full Text: https://doi.org/10.1186/s40478-020-00975-w]
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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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Banfi, S, Bassi, M. T., Andolfi, G., Marchitiello, A., Zanotta, S., Ballabio, A., Casari, G., Franco, B.
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|
<strong>Identification and characterization of AFG3L2, a novel paraplegin-related gene.</strong>
|
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Genomics 59: 51-58, 1999.
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[PubMed: 10395799]
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[Full Text: https://doi.org/10.1006/geno.1999.5818]
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</p>
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<li>
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<p class="mim-text-font">
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Cagnoli, C., Mariotti, C., Taroni, F., Seri, M., Brussino, A., Michielotto, C., Grisoli, M., Di Bella, D., Migone, N., Gellera, C., Di Donato, S., Brusco, A.
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<strong>SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2.</strong>
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Brain 129: 235-242, 2006.
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[PubMed: 16251216]
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[Full Text: https://doi.org/10.1093/brain/awh651]
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<li>
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<p class="mim-text-font">
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Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A.
|
|
<strong>Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias.</strong>
|
|
Hum. Mutat. 31: 1117-1124, 2010.
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[PubMed: 20725928]
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[Full Text: https://doi.org/10.1002/humu.21342]
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</p>
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<li>
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<p class="mim-text-font">
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Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others.
|
|
<strong>ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy.</strong>
|
|
Ann. Neurol. 88: 18-32, 2020.
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[PubMed: 32219868]
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[Full Text: https://doi.org/10.1002/ana.25723]
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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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Charif, M., Roubertie, A., Salime, S., Mamouni, S., Goizet, C., Hamel, C. P., Lenaers, G.
|
|
<strong>A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.</strong>
|
|
Front. Genet. 6: 311, 2015. Note: Electronic Article.
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|
|
[PubMed: 26539208]
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[Full Text: https://doi.org/10.3389/fgene.2015.00311]
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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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Colavito, D., Maritan, V., Suppiej, A., Del Giudice, E., Mazzarolo, M., Miotto, S., Farina, S., Dalle Carbonare, L., Piermarocchi, S., Leon, A.
|
|
<strong>Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.</strong>
|
|
Biomed. Rep. 7: 451-454, 2017.
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|
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[PubMed: 29181157]
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[Full Text: https://doi.org/10.3892/br.2017.987]
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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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Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others.
|
|
<strong>Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.</strong>
|
|
Nature Genet. 42: 313-321, 2010.
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[PubMed: 20208537]
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[Full Text: https://doi.org/10.1038/ng.544]
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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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Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F.
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<strong>Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.</strong>
|
|
Brain 147: 1043-1056, 2024.
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[PubMed: 37804316]
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[Full Text: https://doi.org/10.1093/brain/awad340]
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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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Konig, T., Troder, S. E., Bakka, K., Korwitz, A., Richter-Dennerlein, R., Lampe, P. A., Patron, M., Muhlmeister, M., Guerrero-Castillo, S., Brandt, U., Decker, T., Lauria, I., Paggio, A., Rizzuto, R., Rugarli, E. I., De Stefani, D., Langer, T.
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|
<strong>The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria.</strong>
|
|
Molec. Cell 64: 148-162, 2016.
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[PubMed: 27642048]
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[Full Text: https://doi.org/10.1016/j.molcel.2016.08.020]
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</p>
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<li>
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<p class="mim-text-font">
|
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Koppen, M., Metodiev, M. D., Casari, G., Rugarli, E. I., Langer, T.
|
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<strong>Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia.</strong>
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|
Molec. Cell. Biol. 27: 758-767, 2007.
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[PubMed: 17101804]
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[Full Text: https://doi.org/10.1128/MCB.01470-06]
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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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Martinelli, P., La Mattina, V., Bernacchia, A., Magnoni, R., Cerri, F., Cox, G., Quattrini, A., Casari, G., Rugarli, E. I.
|
|
<strong>Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.</strong>
|
|
Hum. Molec. Genet. 18: 2001-2013, 2009.
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[PubMed: 19289403]
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[Full Text: https://doi.org/10.1093/hmg/ddp124]
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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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Muona, M., Berkovic, S. F., Dibbens, L. M., Oliver, K. L., Maljevic, S., Bayly, M. A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S. E., and 39 others.
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<strong>A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.</strong>
|
|
Nature Genet. 47: 39-46, 2015.
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[PubMed: 25401298]
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[Full Text: https://doi.org/10.1038/ng.3144]
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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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Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others.
|
|
<strong>Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.</strong>
|
|
PLoS Genet. 7: e1002325, 2011. Note: Electronic Article.
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[PubMed: 22022284]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002325]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 07/17/2024<br>Cassandra L. Kniffin - updated : 08/10/2020<br>Patricia A. Hartz - updated : 12/20/2016<br>Cassandra L. Kniffin - updated : 1/16/2015<br>Cassandra L. Kniffin - updated : 2/24/2011<br>Cassandra L. Kniffin - updated : 5/6/2010<br>George E. Tiller - updated : 2/24/2010<br>Patricia A. Hartz - updated : 6/2/2009
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 2/19/2000
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</span>
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</div>
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/17/2024<br>mgross : 03/05/2021<br>carol : 08/17/2020<br>carol : 08/14/2020<br>carol : 08/13/2020<br>ckniffin : 08/10/2020<br>carol : 01/05/2018<br>mgross : 12/20/2016<br>carol : 01/20/2015<br>mcolton : 1/16/2015<br>ckniffin : 1/16/2015<br>terry : 4/10/2012<br>carol : 4/6/2012<br>terry : 3/2/2012<br>carol : 3/2/2012<br>ckniffin : 2/20/2012<br>wwang : 3/18/2011<br>ckniffin : 2/24/2011<br>wwang : 5/18/2010<br>ckniffin : 5/6/2010<br>ckniffin : 5/6/2010<br>wwang : 2/26/2010<br>terry : 2/24/2010<br>mgross : 6/2/2009<br>terry : 6/2/2009<br>cwells : 11/5/2003<br>carol : 2/21/2000
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