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<title>
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Entry
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- *605290 - OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase; OPA1
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- OMIM
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<p>
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<span class="h4">*605290</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605290">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span class="panel-title">
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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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</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=ENSG00000198836;t=ENST00000361510" 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=4976" 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=605290" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="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=ENSG00000198836;t=ENST00000361510" 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_001354663,NM_001354664,NM_015560,NM_130831,NM_130832,NM_130833,NM_130834,NM_130835,NM_130836,NM_130837,XM_047448206,XM_047448207,XM_047448208,XM_047448209,XM_047448210,XM_047448211,XM_047448212,XM_047448213,XM_047448214,XM_047448216" 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_130837" 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=605290" 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=05596&isoform_id=05596_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/OPA1" 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/18860831,18860833,18860835,18860841,34783689,49902674,119598470,119598471,119598472,119598473,119598474,119598475,119598476,119598477,119598478,213508100,213508104,213508106,213508108,215274226,224831243,224831248,224831251,224831253,311346538,311346539,311346540,311346541,311346542,311346543,311346544,311346545,311346547,311346548,311346549,311346550,311346551,311346552,311346553,311346554,311346556,311346557,311346558,311346559,311346560,311346561,311346562,311346563,311346565,311346566,311346567,311346568,311346569,311346570,311346571,311346572,311346574,311346575,311346576,311346577,311346578,311346579,311346580,311346581,311346583,311346584,311346585,311346586,311346587,311346588,311346589,311346590,311346592,311346593,311346594,311346595,311346596,311346597,311346598,311346599,311346601,311346602,311346603,311346604,311346605,311346606,311346607,311346608,311346610,311346611,311346612,311346613,311346614,311346615,311346616,311346617,311346619,311346620,311346621,311346622,311346623,311346624,311346625,311346626,311346628,311346629,311346630,311346631,311346632,311346633,311346634,311346635,311346637,311346638,311346639,311346640,311346641,311346642,311346643,311346644,311346646,311346647,311346648,311346649,311346650,311346651,311346652,311346653,311346655,311346656,311346657,311346658,311346659,311346660,311346661,311346662,311346664,311346665,311346666,311346667,311346668,311346669,311346670,311346671,311346673,311346674,311346675,311346676,311346677,311346678,311346679,311346680,311346682,311346683,311346684,311346685,311346686,311346687,311346688,311346689,311346691,311346692,311346693,311346694,311346695,311346696,311346697,311346698,311346700,311346701,311346702,311346703,311346704,311346705,311346706,311346707,311346709,311346710,311346711,311346712,311346713,311346714,311346715,311346716,311346718,311346719,311346720,311346721,311346722,311346723,311346724,311346725,311346727,311346728,311346729,311346730,311346731,311346732,311346733,311346734,311346736,311346737,311346738,311346739,311346740,311346741,311346742,311346743,311346745,311346746,311346747,311346748,311346749,311346750,311346751,311346752,311346754,311346755,311346756,311346757,311346758,311346759,311346760,311346761,311346763,311346764,311346765,311346766,311346767,311346768,311346769,311346770,311346772,311346773,311346774,311346775,311346776,311346777,311346778,311346779,311346781,311346782,311346783,311346784,311346785,311346786,311346787,311346788,311346790,311346791,311346792,311346793,311346794,311346795,311346796,311346797,311346799,311346800,311346801,311346802,311346803,311346804,311346805,311346806,311346808,311346809,311346810,311346811,311346812,311346813,311346814,311346815,311346817,311346818,311346819,311346820,311346821,311346822,311346823,311346824,311346826,311346827,311346828,311346829,311346830,311346831,311346832,311346833,311346835,311346836,311346837,311346838,311346839,311346840,311346841,311346842,311346844,311346845,311346846,311346847,311346848,311346849,311346850,311346851,311346853,311346854,311346855,311346856,311346857,311346858,311346859,311346860,311346862,311346863,311346864,311346865,311346866,311346867,311346868,311346869,311346871,311346872,311346873,311346874,311346875,311346876,311346877,311346878,311346880,311346881,311346882,311346883,311346884,311346885,311346886,311346887,311346889,311346890,311346891,311346892,311346893,311346894,311346895,311346896,929654047,1233267517,1241781413,2217344076,2217344078,2217344080,2217344082,2217344084,2217344086,2217344088,2217344090,2217344092,2217344094,2462590074,2462590076,2462590078,2462590080,2462590082,2462590084,2462590086,2462590088,2462590090,2462590092,2462590094,2462590096,2462590098,2462590100" 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/O60313" 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=4976" 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=ENSG00000198836;t=ENST00000361510" 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=OPA1" 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=OPA1" 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+4976" 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/OPA1" 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:4976" 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/4976" 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=chr3&hgg_gene=ENST00000361510.8&hgg_start=193593208&hgg_end=193697811&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:8140" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/opa1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605290[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=605290[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/OPA1/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/ENSG00000198836" 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=OPA1" 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=OPA1" 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=OPA1" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://opa1.mitodyn.org" title="eOPA1 - MITOchondrial DYNamics variation pages" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">eOPA1 - MITOchondrial DYNa…</a></div><div style="margin-left: 0.5em;"><a href="http://www.retina-international.org/files/sci-news/opa1mut.htm" title="Mutations of the Optic Atrophy 1 Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Mutations of the Optic Atr…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=OPA1&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/PA31927" 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:8140" 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/FBgn0261276.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:1921393" 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/OPA1#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:1921393" 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/4976/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://omia.org/OMIA002871/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4976" 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=WBGene00001134;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-041114-7" 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 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:4976" 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=OPA1&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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<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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<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> 715374003, 717336005<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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605290
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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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OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase; OPA1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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OPA1 GENE<br />
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KIAA0567<br />
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DYNAMIN-LIKE 120-KD PROTEIN, MITOCHONDRIAL
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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=OPA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">OPA1</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>
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Cytogenetic location: <a href="/geneMap/3/975?start=-3&limit=10&highlight=975">3q29</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:193593208-193697811&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'})">3:193,593,208-193,697,811</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=616896,606657,210000,165500,125250" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
|
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<span class="mim-font">
|
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<a href="/geneMap/3/975?start=-3&limit=10&highlight=975">
|
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3q29
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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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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<a href="/entry/616896"> 616896 </a>
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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="Autosomal recessive">AR</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>
|
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<span class="mim-font">
|
|
{Glaucoma, normal tension, susceptibility to}
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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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<a href="/entry/606657"> 606657 </a>
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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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</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>
|
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<span class="mim-font">
|
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Behr syndrome
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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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|
|
<a href="/entry/210000"> 210000 </a>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Optic atrophy 1
|
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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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|
|
<a href="/entry/165500"> 165500 </a>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
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<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">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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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">
|
|
Optic atrophy plus syndrome
|
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/125250"> 125250 </a>
|
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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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|
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<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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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605290" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605290" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The OPA1 gene encodes a protein that localizes to the inner mitochondrial membrane and regulates several important cellular processes including stability of the mitochondrial network, mitochondrial bioenergetic output, and sequestration of proapoptotic cytochrome c oxidase molecules within the mitochondrial cristae spaces (summary by <a href="#52" class="mim-tip-reference" title="Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others. <strong>Multi-system neurological disease is common in patients with OPA1 mutations.</strong> Brain 133: 771-786, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20157015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20157015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20157015[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/awq007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20157015">Yu-Wai-Man et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20157015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By sequencing clones obtained from a size-fractionated brain cDNA library, <a href="#33" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 31-39, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628581</a>] [<a href="https://doi.org/10.1093/dnares/5.1.31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628581">Nagase et al. (1998)</a> cloned OPA1, which they designated KIAA0567. The deduced protein contained 978 amino acids. RT-PCR detected highest OPA1 expression in heart and kidney, with low expression in all other tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9628581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the fission yeast S. pombe, Pelloquin et al. (<a href="#38" class="mim-tip-reference" title="Pelloquin, L., Belenguer, P., Menon, Y., Ducommun, B. <strong>Identification of a fission yeast dynamin-related protein involved in mitochondrial DNA maintenance.</strong> Biochem. Biophys. Res. Commun. 251: 720-726, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790976</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790976">1998</a>, <a href="#39" class="mim-tip-reference" title="Pelloquin, L., Belenguer, P., Menon, Y., Gas, N., Ducommun, B. <strong>Fission yeast Msp1 is a mitochondrial dynamin-related protein.</strong> J. Cell Sci. 112: 4151-4161, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10547374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10547374</a>] [<a href="https://doi.org/10.1242/jcs.112.22.4151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10547374">1999</a>) identified a dynamin-related protein, Msp1, essential for the maintenance of mitochondrial DNA, as is true for Mgm1p, its ortholog in S. cerevisiae (<a href="#25" class="mim-tip-reference" title="Jones, B. A., Fangman, W. L. <strong>Mitochondrial DNA maintenance in yeast requires a protein containing a region related to the GTP-binding domain of dynamin.</strong> Genes Dev. 6: 380-389, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532158</a>] [<a href="https://doi.org/10.1101/gad.6.3.380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1532158">Jones and Fangman, 1992</a>). Both proteins have a GTPase and a central dynamin domain conserved among all dynamins and a highly basic N-terminal domain required for mitochondrial localization. <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> searched for a human Msp1/Mgm1p homolog in nucleotide databases and identified the KIAA0567 cDNA previously cloned by <a href="#33" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 31-39, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628581</a>] [<a href="https://doi.org/10.1093/dnares/5.1.31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628581">Nagase et al. (1998)</a>. The 960-amino acid protein shared 19% and 17% identity to Msp1 and Mgm1p, respectively. <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> then retrieved the sequence of the gene, which they referred to as OPA1, in 2 overlapping clones from the Whitehead Institute server. Labeling studies indicated that Opa1 is a component of the mitochondrial network. Mitochondrial localization of OPA1 was also consistent with a ubiquitous expression of its transcripts in all tissues examined by Northern blot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9628581+10547374+9790976+11017079+1532158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> established a PAC contig covering the entire optic atrophy-1 (<a href="/entry/165500">165500</a>) candidate region of approximately 1 Mb. By a sequence skimming approach, they independently identified the the OPA1 gene, encoding a polypeptide with homology to dynamin-related GTPases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR of human RNA, <a href="#15" class="mim-tip-reference" title="Delettre, C., Griffoin, J.-M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., Lenaers, G., Belenguer, P., Hamel, C. P. <strong>Mutation spectrum and splicing variants in the OPA1 gene.</strong> Hum. Genet. 109: 584-591, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810270</a>] [<a href="https://doi.org/10.1007/s00439-001-0633-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810270">Delettre et al. (2001)</a> cloned 8 OPA1 variants resulting from alternative splicing of exons 4, 4b, and 5b. All 8 OPA1 isoforms contain an N-terminal mitochondrial leader sequence, a central coiled-coil region, a GTPase domain, a dynamin central region, and a C-terminal coiled-coil region. Exons 4b and 5b encode 18- and 37-amino acid sequences, respectively. The sequence encoded by exon 5b was predicted to form a coiled-coil. RT-PCR detected variable expression of all 8 OPA1 variants in the 11 tissues tested. In retina, heart, skeletal muscle, lung, ovary, and fetal brain, variants 3/4/5/6 and 3/5/5b/6, in which the numbers indicate the exons present from exon 3 to exon 6, showed highest expression. In kidney, liver, and colon, variant 3/4/5/5b/6 showed highest expression. Except in skeletal muscle, variants 3/4b/5/5b/6 and 3/4/4b/5/6 showed low expression. Variants 3/5/6 and 3/4b/5/6 were weakly expressed in all tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11810270" 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="#36" class="mim-tip-reference" title="Olichon, A., ElAchouri, G., Baricault, L., Delettre, C., Belenguer, P., Lenaers, G. <strong>OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.</strong> Cell Death Differ. 14: 682-692, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17024226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17024226</a>] [<a href="https://doi.org/10.1038/sj.cdd.4402048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17024226">Olichon et al. (2007)</a> further characterized the 8 OPA1 splice variants. They reported that all 8 OPA1 isoforms have a transmembrane domain immediately following the N-terminal mitochondrial targeting signal. The isoforms differ only in the presence or absence of domains 4, 4b, and 5b, which are encoded by exons 4, 4b, and 5b, respectively, within the region between the transmembrane domain and the central coiled-coil region. <a href="#36" class="mim-tip-reference" title="Olichon, A., ElAchouri, G., Baricault, L., Delettre, C., Belenguer, P., Lenaers, G. <strong>OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.</strong> Cell Death Differ. 14: 682-692, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17024226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17024226</a>] [<a href="https://doi.org/10.1038/sj.cdd.4402048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17024226">Olichon et al. (2007)</a> also presented evidence suggesting that short forms of the OPA1 isoforms are produced by proteolytic processing. Exon-specific qualitative PCR revealed tissue-specific expression of OPA1 variants, with variant 3/4/4b/6 predominating in brain, variant 3/4/5/6 predominating in heart, and variant 3/4/5b/6 predominating in liver, kidney, and thymus. Phylogenetic analysis revealed that exon 4 is conserved throughout evolution, whereas exons 4b and 5b are vertebrate specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17024226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Elachouri, G., Vidoni, S., Zanna, C., Pattyn, A., Boukhaddaoui, H., Gaget, K., Yu-Wai-Man, P., Gasparre, G., Sarzi, E., Delettre, C., Olichon, A., Loiseau, D., Reynier, P., Chinnery, P. F., Rotig, A., Carelli, V., Hamel, C. P., Rugolo, M., Lenaers, G. <strong>OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution.</strong> Genome Res. 21: 12-20, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20974897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20974897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20974897[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.108696.110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20974897">Elachouri et al. (2011)</a> stated that the common C-terminal domain found in all OPA1 isoforms contains a GTPase domain and a GTPase effector domain (GED). They also reported that exon 4b encodes a second transmembrane domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20974897" 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="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> stated that the OPA1 gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Delettre, C., Griffoin, J.-M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., Lenaers, G., Belenguer, P., Hamel, C. P. <strong>Mutation spectrum and splicing variants in the OPA1 gene.</strong> Hum. Genet. 109: 584-591, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810270</a>] [<a href="https://doi.org/10.1007/s00439-001-0633-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810270">Delettre et al. (2001)</a> reported that the OPA1 gene contains 31 exons, including the alternatively spliced exons 4, 4b, and 5b. The last exon in noncoding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11810270" 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 fluorescence in situ hybridization, <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> mapped the OPA1 gene to chromosome 3q28-q29, the region to which the locus for optic atrophy-1 had been mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017079" 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="#35" class="mim-tip-reference" title="Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., Lenaers, G. <strong>Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis.</strong> J. Biol. Chem. 278: 7743-7746, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509422</a>] [<a href="https://doi.org/10.1074/jbc.C200677200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12509422">Olichon et al. (2003)</a> determined that the downregulation of OPA1 in HeLa cells with expression of specific small interfering RNA (siRNA) leads to fragmentation of the mitochondrial network, dissipation of the mitochondrial membrane potential, and disorganization of the cristae. These events were followed by cytochrome c (<a href="/entry/123970">123970</a>) release and caspase (see <a href="/entry/600636">600636</a>)-dependent apoptotic nuclear events. In a human ovarian carcinoma cell line, siRNA-induced apoptosis was inhibited by BCL2 (<a href="/entry/151430">151430</a>) overexpression. <a href="#35" class="mim-tip-reference" title="Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., Lenaers, G. <strong>Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis.</strong> J. Biol. Chem. 278: 7743-7746, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509422</a>] [<a href="https://doi.org/10.1074/jbc.C200677200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12509422">Olichon et al. (2003)</a> concluded that OPA1 is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity. As the loss of OPA1 committed cells to apoptosis without any other stimulus, <a href="#35" class="mim-tip-reference" title="Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., Lenaers, G. <strong>Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis.</strong> J. Biol. Chem. 278: 7743-7746, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509422</a>] [<a href="https://doi.org/10.1074/jbc.C200677200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12509422">Olichon et al. (2003)</a> proposed that OPA1 is involved in the sequestration of cytochrome c, and that OPA1 may be a target for mitochondrial apoptotic effectors. They also proposed that abnormal apoptosis is a likely process leading to the retinal ganglion cell degeneration in autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>) patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12509422" 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="#30" class="mim-tip-reference" title="Meeusen, S., McCaffery, J. M., Nunnari, J. <strong>Mitochondrial fusion intermediates revealed in vitro.</strong> Science 305: 1747-1752, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15297626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15297626</a>] [<a href="https://doi.org/10.1126/science.1100612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15297626">Meeusen et al. (2004)</a> captured mitochondrial fusion in vitro in transgenic experiments using yeast mitochondria. They found that mitochondrial outer and inner membrane fusion events were separable and mechanistically distinct, but both required GTP hydrolysis. Homotypic trans interactions of the ancient outer transmembrane GTPase, Fzo1 (see MFN1; <a href="/entry/608506">608506</a>), were required to promote the fusion of mitochondrial outer membranes, whereas electrical potential was also required for fusion of inner membranes. <a href="#30" class="mim-tip-reference" title="Meeusen, S., McCaffery, J. M., Nunnari, J. <strong>Mitochondrial fusion intermediates revealed in vitro.</strong> Science 305: 1747-1752, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15297626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15297626</a>] [<a href="https://doi.org/10.1126/science.1100612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15297626">Meeusen et al. (2004)</a> found that outer membrane fusion required GTP and trans Fzo interactions on opposing mitochondria, suggesting that GTP promotes outer membrane fusion by means of Fzo1. The only known fusion protein associated with the inner membrane is the dynamin-related GTPase protein (DRP) Mgm1, of which OPA1 is the human ortholog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15297626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Cipolat, S., Martins de Brito, O., Dal Zilio, B., Scorrano, L. <strong>OPA1 requires mitofusin 1 to promote mitochondrial fusion.</strong> Proc. Nat. Acad. Sci. 101: 15927-15932, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15509649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15509649</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15509649[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407043101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15509649">Cipolat et al. (2004)</a> determined that both the GTPase domain and the C-terminal coiled-coil domain of mouse Opa1 were required to promote the formation of branched network of elongated mitochondria in mouse embryonic fibroblasts. Stable reduction of Opa1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. The level of Opa1 did not affect mitochondrial docking, but it correlated with the extent of mitochondrial fusion. Using RNA interference against mouse Opa1 in Mfn1-null mouse embryonic fibroblasts, <a href="#13" class="mim-tip-reference" title="Cipolat, S., Martins de Brito, O., Dal Zilio, B., Scorrano, L. <strong>OPA1 requires mitofusin 1 to promote mitochondrial fusion.</strong> Proc. Nat. Acad. Sci. 101: 15927-15932, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15509649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15509649</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15509649[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407043101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15509649">Cipolat et al. (2004)</a> demonstrated an interdependence between Opa1 and Mfn1 in promoting mitochondrial elongation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15509649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse embryonic fibroblasts, <a href="#19" class="mim-tip-reference" title="Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., Bartoli, D., Polishuck, R. S., Danial, N. N., De Strooper, B., Scorrano, L. <strong>OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.</strong> Cell 126: 177-189, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16839885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16839885</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16839885">Frezza et al. (2006)</a> showed that Opa1 regulated apoptosis by controlling cristae remodeling and cytochrome c redistribution. This function correlated with Opa1 oligomerization and was dependent on cleavage of Opa1 by Parl (<a href="/entry/607858">607858</a>). <a href="#19" class="mim-tip-reference" title="Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., Bartoli, D., Polishuck, R. S., Danial, N. N., De Strooper, B., Scorrano, L. <strong>OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.</strong> Cell 126: 177-189, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16839885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16839885</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16839885">Frezza et al. (2006)</a> concluded that oligomerization of OPA1 regulates apoptosis by maintaining the tightness of cristae junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16839885" 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="#36" class="mim-tip-reference" title="Olichon, A., ElAchouri, G., Baricault, L., Delettre, C., Belenguer, P., Lenaers, G. <strong>OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.</strong> Cell Death Differ. 14: 682-692, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17024226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17024226</a>] [<a href="https://doi.org/10.1038/sj.cdd.4402048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17024226">Olichon et al. (2007)</a> found that silencing of exon 4-containing OPA1 variants in HeLa cells led to the disappearance of the 4 most abundant OPA1 isoforms, whereas silencing of variants containing exon 4b or 5b had little effect. Overexpression and knockdown studies showed that OPA1 isoforms containing domain 4, but not those containing domain 4b or 5b, were involved in maintenance of the mitochondrial membrane potential and fusion of the mitochondrial network. Conversely, knockdown of variants containing exon 4b or 5b led to apoptosis in the absence of mitochondrial morphologic changes or dissipation of the membrane potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17024226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using conditional gene targeting, <a href="#32" class="mim-tip-reference" title="Merkwirth, C., Dargazanli, S., Tatsuta, T., Geimer, S., Lower, B., Wunderlich, F. T., von Kleist-Retzow, J.-C., Waisman, A., Westermann, B., Langer, T. <strong>Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria.</strong> Genes Dev. 22: 476-488, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18281461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18281461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18281461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.460708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18281461">Merkwirth et al. (2008)</a> restricted expression of mouse prohibitin-2 (PHB2; <a href="/entry/610704">610704</a>) to mitochondria and identified processing of Opa1 as the central cellular process controlled by prohibitins. Deletion of Phb2 led to selective loss of long isoforms of Opa1, resulting in aberrant cristae morphogenesis, impaired cellular proliferation, and resistance to apoptosis. Expression of a long Opa1 isoform in Phb2-deficient cells suppressed these defects, identifying impaired Opa1 processing as the primary cellular defect in the absence of prohibitins. <a href="#32" class="mim-tip-reference" title="Merkwirth, C., Dargazanli, S., Tatsuta, T., Geimer, S., Lower, B., Wunderlich, F. T., von Kleist-Retzow, J.-C., Waisman, A., Westermann, B., Langer, T. <strong>Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria.</strong> Genes Dev. 22: 476-488, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18281461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18281461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18281461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.460708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18281461">Merkwirth et al. (2008)</a> concluded that prohibitins are essential for Opa1-dependent formation of mitochondrial cristae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18281461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunostaining, <a href="#2" class="mim-tip-reference" title="Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P. <strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong> Ann. Neurol. 58: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240368</a>] [<a href="https://doi.org/10.1002/ana.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240368">Amati-Bonneau et al. (2005)</a> found that the OPA1 protein was ubiquitously distributed in sensory and neural cochlear cells of the guinea pig. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240368" 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>Mitochondrial nucleoids are autonomous replication units that contain 6 to 10 copies of mitochondrial DNA (mtDNA) and associated proteins. <a href="#17" class="mim-tip-reference" title="Elachouri, G., Vidoni, S., Zanna, C., Pattyn, A., Boukhaddaoui, H., Gaget, K., Yu-Wai-Man, P., Gasparre, G., Sarzi, E., Delettre, C., Olichon, A., Loiseau, D., Reynier, P., Chinnery, P. F., Rotig, A., Carelli, V., Hamel, C. P., Rugolo, M., Lenaers, G. <strong>OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution.</strong> Genome Res. 21: 12-20, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20974897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20974897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20974897[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.108696.110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20974897">Elachouri et al. (2011)</a> found that a 10-kD peptide generated by proteolytic processing of an OPA1 isoform containing domain 4b localized to mitochondrial nucleoids. This peptide, designated NT-OPA1-exon4b, was generated by proteolytic removal of the mitochondrial localization signal followed by YME1L (<a href="/entry/607472">607472</a>)-mediated cleavage within the exon 5-encoded domain, which released the C-terminal GTPase domain and GED. Fractionation and biochemical analysis showed that NT-OPA1-exon4b bound to the inner mitochondrial membrane, and chromatin immunoprecipitation studies showed that it also bound to nucleoid DNA. Knockdown of exon 4b-containing OPA1 variants inhibited mtDNA replication and altered the size and distribution of nucleoids. <a href="#17" class="mim-tip-reference" title="Elachouri, G., Vidoni, S., Zanna, C., Pattyn, A., Boukhaddaoui, H., Gaget, K., Yu-Wai-Man, P., Gasparre, G., Sarzi, E., Delettre, C., Olichon, A., Loiseau, D., Reynier, P., Chinnery, P. F., Rotig, A., Carelli, V., Hamel, C. P., Rugolo, M., Lenaers, G. <strong>OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution.</strong> Genome Res. 21: 12-20, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20974897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20974897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20974897[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.108696.110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20974897">Elachouri et al. (2011)</a> concluded that NT-OPA1-exon4b influences replication of mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20974897" 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="Ban, T., Heymann, J. A. W., Song, Z., Hinshaw, J. E., Chan, D. C. <strong>OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.</strong> Hum. Molec. Genet. 19: 2113-2122, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185555">Ban et al. (2010)</a> showed that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids, such as cardiolipin. Lipid association triggered assembly of OPA1 into higher order oligomers. In addition, OPA1 could promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies were observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 was suppressed by GTP-gamma-S. OPA1 disease alleles associated with dominant optic atrophy displayed selective defects in several activities, including cardiolipin association, GTP hydrolysis, and membrane tubulation. <a href="#8" class="mim-tip-reference" title="Ban, T., Heymann, J. A. W., Song, Z., Hinshaw, J. E., Chan, D. C. <strong>OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.</strong> Hum. Molec. Genet. 19: 2113-2122, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185555">Ban et al. (2010)</a> concluded that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis, and lead to membrane deformation into tubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20185555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mfn1 (<a href="/entry/608506">608506</a>) and Mfn2 (<a href="/entry/608507">608507</a>) in the embryonic mouse heart, or gene trapping of Mfn2 or Opa1 in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (<a href="/entry/190180">190180</a>)/Bmp (see <a href="/entry/112264">112264</a>), serum response factor (SRF; <a href="/entry/600589">600589</a>), Gata4 (<a href="/entry/600576">600576</a>), and myocyte enhancer factor-2, linked to increased calcium-dependent calcineurin (see <a href="/entry/114105">114105</a>) activity and Notch1 (<a href="/entry/190198">190198</a>) signaling that impaired embryonic stem cell differentiation. <a href="#26" class="mim-tip-reference" title="Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W., II, Scorrano, L. <strong>Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.</strong> Science 342: 734-737, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24091702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24091702</a>] [<a href="https://doi.org/10.1126/science.1241359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24091702">Kasahara et al. (2013)</a> concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24091702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S., van der Bliek, A. M. <strong>Inducible proteolytic activation of OPA1 mediated by the OMA1 protease in mammalian cells.</strong> J. Cell Biol. 187: 959-966, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20038677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20038677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20038677[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.200906083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20038677">Head et al. (2009)</a> found that human OMA1 (<a href="/entry/617081">617081</a>) is the protease that cleaves long isoforms of OPA1 in response to mitochondrial stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20038677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="An, H.-J., Cho, G., Lee, J.-O., Paik, S.-G., Kim, Y. S., Lee, H. <strong>Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria.</strong> Proc. Nat. Acad. Sci. 110: 13014-12019, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23878241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23878241</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23878241[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1307170110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23878241">An et al. (2013)</a> found that knockdown of HIGD1A (<a href="/entry/618623">618623</a>) in HEK293T and HeLa cells resulted in mitochondria fragmentation, disorganization of mitochondrial cristae, and inhibition of proliferation. HIGD1A knockdown led to cleavage of OPA1, resulting in loss of the OPA1 long isoform and accumulation of small soluble forms. Overexpression of HIGD1A partially inhibited OPA1 cleavage, conserved mitochondrial morphology, and prolonged cell survival. Immunoprecipitation and mutation analyses demonstrated that the N-terminal tail of HIGD1A bound OPA1. Overexpression of a noncleavable long OPA1 isoform alleviated growth retardation in HIGD1A-knockdown HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23878241" 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 nonstressed cells, the mitochondrial intermembrane space is locked inside cristae by protein complexes containing the long isoform of OPA1 (L-OPA1). Using U2OS human osteosarcoma cells engineered to inducibly express BIM (BCL2L11; <a href="/entry/603827">603827</a>), which is the upstream activator of proapoptotic BAX-BAK1, <a href="#23" class="mim-tip-reference" title="Jiang, X., Jiang, H., Shen, Z., Wang, X. <strong>Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis.</strong> Proc. Nat. Acad. Sci. 111: 14782-14787, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25275009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25275009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25275009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1417253111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25275009">Jiang et al. (2014)</a> found that OMA1 was required for L-OPA1 cleavage and BIM-dependent apoptosis. Short hairpin-mediated knockdown of OMA1, or CRISPR-mediated deletion of OMA1, abrogated BIM-dependent cleavage of L-OPA1, disassembly of OPA1-containing complexes, cytochrome c and SMAC (DIABLO; <a href="/entry/605219">605219</a>) release from mitochondria, and mitochondrial fragmentation. Further knockdown and mutation studies supported the critical role of OMA1 downstream of BIM and BAX-BAK1 in L-OPA1 cleavage and release from cristae protein complexes, and loss of mitochondrial membrane permeability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25275009" 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>Both YME1L1 (<a href="/entry/607472">607472</a>) and OMA1 convert long forms of OPA1 to short forms of OPA1. <a href="#51" class="mim-tip-reference" title="Wai, T., Garcia-Prieto, J., Baker, M. J., Merkwirth, C., Benit, P., Rustin, P., Ruperez, F. J., Barbas, C., Ibanez, B., Langer, T. <strong>Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.</strong> Science 350: aad0116, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785494</a>] [<a href="https://doi.org/10.1126/science.aad0116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785494">Wai et al. (2015)</a> found that targeted deletion of Yme1l in mouse cardiomyocytes induced proteolytic cleavage of Opa1 by Oma1 and drove fragmentation of mitochondria. Ymel1 mutant mice suffered from dilated cardiomyopathy, heart failure, and early death, with a metabolic switch from fatty oxidation toward glucose utilization. Cardiac function, longevity, and metabolic profiles in Yme1l mice were reversed by supplemental deletion of Yme1l in skeletal muscle, an insulin-signaling tissue, although fragmented mitochondria were detected in Yme1l knockout cardiomyocytes. Feeding a high-fat diet to cardiomyocyte knockout Yme1l mutant mice also protected them from cardiac and metabolic defects, without restoring mitochondrial morphology. Knockout of both Oma1 and Yme1l in cardiomyocytes prevented conversion of L-Opa1 to S-Opa1 forms and restored normal mitochondrial architecture, in addition to protecting Yme1l mutant mice from cardiomyopathy and early death. <a href="#51" class="mim-tip-reference" title="Wai, T., Garcia-Prieto, J., Baker, M. J., Merkwirth, C., Benit, P., Rustin, P., Ruperez, F. J., Barbas, C., Ibanez, B., Langer, T. <strong>Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.</strong> Science 350: aad0116, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785494</a>] [<a href="https://doi.org/10.1126/science.aad0116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785494">Wai et al. (2015)</a> concluded that mitochondrial fusion mediated by L-OPA1 preserves cardiac function, whereas its stress-induced processing by OMA1 and mitochondrial fragmentation triggers dilated cardiomyopathy and heart failure, and that deleterious effects of mitochondrial fragmentation in cardiomyocytes can be circumvented by metabolic intervention. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26785494" 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>Heterozygous OPA1 Mutations</em></strong></p><p>
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In 6 unrelated families with dominant optic atrophy, <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> identified 4 different heterozygous mutations in the OPA1 gene (<a href="#0001">605290.0001</a>-<a href="#0004">605290.0004</a>). One of the mutations was found in 3 families who were apparently unrelated but who all originated from the northern French provinces and Belgium. <a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> identified mutations in the OPA1 gene in 7 independent families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11017080+11017079" 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="#40" class="mim-tip-reference" title="Pesch, U. E. A., Leo-Kottler, B., Mayer, S., Jurklies, B., Kellner, U., Apfelstedt-Sylla, E., Zrenner, E., Alexander, C., Wissinger, B. <strong>OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.</strong> Hum. Molec. Genet. 10: 1359-1368, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440988</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440988">Pesch et al. (2001)</a> identified heterozygous mutations in the OPA1 gene in 25 of 78 independent autosomal dominant optic atrophy families screened. Most missense mutations clustered within the putative GTPase domain, and there was a preponderance of mutations that resulted in premature translation termination. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation. Their observations supported the notion that haploinsufficiency may represent a major pathomechanism for dominant optic atrophy. In addition, <a href="#40" class="mim-tip-reference" title="Pesch, U. E. A., Leo-Kottler, B., Mayer, S., Jurklies, B., Kellner, U., Apfelstedt-Sylla, E., Zrenner, E., Alexander, C., Wissinger, B. <strong>OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.</strong> Hum. Molec. Genet. 10: 1359-1368, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440988</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440988">Pesch et al. (2001)</a> identified a patient who was a compound heterozygote for 2 OPA1 missense mutations. The patient was much more severely affected than her simple heterozygotic parents and sibs, implying that these OPA1 alleles can behave semidominantly or recessively rather than purely dominantly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440988" 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="#48" class="mim-tip-reference" title="Toomes, C., Marchbank, N. J., Mackey, D. A., Craig, J. E., Newbury-Ecob, R. A., Bennett, C. P., Vize, C. J., Desai, S. P., Black, G. C. M., Patel, N., Teimory, M., Markham, A. F., Inglehearn, C. F., Churchill, A. J. <strong>Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.</strong> Hum. Molec. Genet. 10: 1369-1378, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440989</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440989">Toomes et al. (2001)</a> found mutations in OPA1 in 20 of 35 dominant optic atrophy patients screened. The predominance of null mutations further suggests that the mechanism underlying optic atrophy is haploinsufficiency. To investigate whether LHON could be caused by mutations in OPA1, the authors also screened a panel of 28 LHON patients who tested negatively for the 3 major LHON mutations. No mutations were identified in any LHON patients, indicating that dominant optic atrophy and LHON are genetically distinct. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Delettre, C., Griffoin, J.-M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., Lenaers, G., Belenguer, P., Hamel, C. P. <strong>Mutation spectrum and splicing variants in the OPA1 gene.</strong> Hum. Genet. 109: 584-591, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810270</a>] [<a href="https://doi.org/10.1007/s00439-001-0633-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810270">Delettre et al. (2001)</a> screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found 15 different mutations, 8 of which were novel, in 17 (89%) patients. Most of the mutations were truncating (65%) and located in exons 8 to 28, but a number of them were amino acid changed located predominantly in the GTPase domain in exons 8 to 15. <a href="#15" class="mim-tip-reference" title="Delettre, C., Griffoin, J.-M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., Lenaers, G., Belenguer, P., Hamel, C. P. <strong>Mutation spectrum and splicing variants in the OPA1 gene.</strong> Hum. Genet. 109: 584-591, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810270</a>] [<a href="https://doi.org/10.1007/s00439-001-0633-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810270">Delettre et al. (2001)</a> hypothesized that at least 2 modifications of OPA1 may lead to dominant optic atrophy: alteration in GTPase activity and loss of the last 7 C-terminal amino acids that putatively interact with other proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11810270" 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="#44" class="mim-tip-reference" title="Shimizu, S., Mori, N., Kishi, M., Sugata, H., Tsuda, A., Kubota, N. <strong>A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy.</strong> Am. J. Ophthal. 135: 256-257, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566046</a>] [<a href="https://doi.org/10.1016/s0002-9394(02)01929-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566046">Shimizu et al. (2003)</a>, <a href="#27" class="mim-tip-reference" title="Li, C., Kosmorsky, G., Zhang, K., Katz, B. J., Ge, J., Traboulsi, E. I. <strong>Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation.</strong> Am. J. Med. Genet. 138A: 208-211, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16158427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16158427</a>] [<a href="https://doi.org/10.1002/ajmg.a.30794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16158427">Li et al. (2005)</a>, and <a href="#2" class="mim-tip-reference" title="Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P. <strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong> Ann. Neurol. 58: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240368</a>] [<a href="https://doi.org/10.1002/ana.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240368">Amati-Bonneau et al. (2005)</a> identified the same heterozygous mutation in the OPA1 gene (R445H; <a href="#0011">605290.0011</a>) in several unrelated patients with optic atrophy, deafness, and neuromuscular complications (<a href="/entry/125250">125250</a>), suggesting that this mutation is specifically associated with the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16240368+12566046+16158427" 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 patients with dominant optic atrophy, <a href="#43" class="mim-tip-reference" title="Schimpf, S., Schaich, S., Wissinger, B. <strong>Activation of cryptic splice sites is a frequent splicing defect mechanism caused by mutations in exon and intron sequences of the OPA1 gene.</strong> Hum. Genet. 118: 767-771, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16323009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16323009</a>] [<a href="https://doi.org/10.1007/s00439-005-0096-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16323009">Schimpf et al. (2006)</a> identified and characterized 4 intronic and 3 exonic OPA1 gene mutations that caused a variety of splicing defects and transcript processing defects, including activation of cryptic splice sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16323009" 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="#42" class="mim-tip-reference" title="Schimpf, S., Fuhrmann, N., Schaich, S., Wissinger, B. <strong>Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons.</strong> Hum. Mutat. 29: 106-112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722006</a>] [<a href="https://doi.org/10.1002/humu.20607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722006">Schimpf et al. (2008)</a> analyzed OPA1 transcripts from 37 different OPA1 mutations, including 22 novel mutations, from 42 OPA1 patients or families. These included 11 missense, 3 nonsense, and 15 splice site mutations, and 7 deletions and/or insertions. All missense mutations were located in the GTPase domain: 8 resulted in an amino acid exchange, and 3 were in the last or penultimate nucleotide of an exon, resulting in a leaky splice defect. Eleven splice site mutations resulted in complete skipping of an adjacent exon, whereas 4 resulted in activation of a cryptic splice site. Using pyrosequencing technology, <a href="#42" class="mim-tip-reference" title="Schimpf, S., Fuhrmann, N., Schaich, S., Wissinger, B. <strong>Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons.</strong> Hum. Mutat. 29: 106-112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722006</a>] [<a href="https://doi.org/10.1002/humu.20607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722006">Schimpf et al. (2008)</a> demonstrated that nonsense or frameshift mutations were associated with a 20 to 50% reduced level of mutant mRNA transcripts in corresponding patient samples, although these levels varied between family members with the same mutation and between blood and lymphoblastoid cells from the same individual. RNA transcripts from lymphoblastoid cells were less stable compared to blood samples. These findings suggested that nonsense-mediated decay occurs to a different degree depending on specific mutation type or location, as well as cell or tissue type. <a href="#42" class="mim-tip-reference" title="Schimpf, S., Fuhrmann, N., Schaich, S., Wissinger, B. <strong>Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons.</strong> Hum. Mutat. 29: 106-112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722006</a>] [<a href="https://doi.org/10.1002/humu.20607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722006">Schimpf et al. (2008)</a> concluded that haploinsufficiency of OPA1 is the pathomechanism in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17722006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation probe amplification (MLPA), <a href="#20" class="mim-tip-reference" title="Fuhrmann, N., Alavi, M. V., Bitoun, P., Woernle, S., Auburger, G., Leo-Kottler, B., Yu-Wai-Man, P., Chinnery, P., Wissinger, B. <strong>Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy.</strong> J. Med. Genet. 46: 136-144, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19181907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19181907</a>] [<a href="https://doi.org/10.1136/jmg.2008.062570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19181907">Fuhrmann et al. (2009)</a> identified heterozygous deletions of 1 or more exons in the OPA1 gene in 5 of 42 OPA1 probands who did not have point mutations by previous screening techniques. Three additional probands had a heterozygous in-frame duplication of exons 7 to 9. Overall, the results were consistent with haploinsufficiency as a disease mechanism rather than gain of function. <a href="#20" class="mim-tip-reference" title="Fuhrmann, N., Alavi, M. V., Bitoun, P., Woernle, S., Auburger, G., Leo-Kottler, B., Yu-Wai-Man, P., Chinnery, P., Wissinger, B. <strong>Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy.</strong> J. Med. Genet. 46: 136-144, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19181907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19181907</a>] [<a href="https://doi.org/10.1136/jmg.2008.062570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19181907">Fuhrmann et al. (2009)</a> estimated that OPA1 genomic rearrangements have a prevalence of 12.9% in patients with autosomal dominant optic atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19181907" 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="#53" class="mim-tip-reference" title="Yu-Wai-Man, P., Sitarz, K. S., Samuels, D. C., Griffiths, P. G., Reeve, A. K., Bindoff, L. A., Horvath, R., Chinnery, P. F. <strong>OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules.</strong> Hum. Molec. Genet. 19: 3043-3052, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484224[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20484224">Yu-Wai-Man et al. (2010)</a> investigated the mtDNA changes induced by OPA1 mutations in skeletal muscle biopsies from 15 patients with either isolated dominant optic atrophy (DOA; <a href="/entry/165500">165500</a>) or the multisystem neurologic disorder DOA+ (<a href="/entry/125250">125250</a>). There was a 2- to 4-fold increase in mtDNA copy number at the single-fiber level, and patients with DOA+ features had significantly greater mtDNA proliferation in their cytochrome c oxidase (COX; see <a href="/entry/516030">516030</a>)-negative skeletal muscle fibers compared to patients with isolated optic neuropathy. Low levels of wildtype mtDNA molecules were present in COX-deficient muscle fibers from both isolated DOA and DOA+ patients, implicating haploinsufficiency as the mechanism responsible for the biochemical defect. The authors suggested that their findings were consistent with a 'maintenance of wildtype' hypothesis, with secondary mtDNA deletions induced by OPA1 mutations triggering a compensatory mitochondrial proliferative response to maintain an optimal level of wildtype mtDNA genomes. However, when deletion levels reach a critical level, further mitochondrial proliferation may lead to replication of the mutant species at the expense of wildtype mtDNA, resulting in the loss of respiratory chain COX activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484224" 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 27-year-old Italian woman and her 57-year-old mother with DOA+, <a href="#34" class="mim-tip-reference" title="Napolitano, F., Terracciano, C., Bruno, G., Nesti, C., Barillari, M. R., Barillari, U., Santorelli, F. M., Melone, M. A. B., Esposito, T., Sampaolo, S. <strong>Intrafamilial 'DOA-plus' phenotype variability related to different OMI/HTRA2 expression.</strong> Am. J. Med. Genet. 182A: 176-182, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31609081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31609081</a>] [<a href="https://doi.org/10.1002/ajmg.a.61381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31609081">Napolitano et al. (2020)</a> identified heterozygosity for a missense mutation in the OPA1 gene (R445H; <a href="#0011">605290.0011</a>). The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (<a href="/entry/606441">606441</a>) was increased in the muscle tissue of both patients, although more so in the daughter. <a href="#34" class="mim-tip-reference" title="Napolitano, F., Terracciano, C., Bruno, G., Nesti, C., Barillari, M. R., Barillari, U., Santorelli, F. M., Melone, M. A. B., Esposito, T., Sampaolo, S. <strong>Intrafamilial 'DOA-plus' phenotype variability related to different OMI/HTRA2 expression.</strong> Am. J. Med. Genet. 182A: 176-182, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31609081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31609081</a>] [<a href="https://doi.org/10.1002/ajmg.a.61381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31609081">Napolitano et al. (2020)</a> hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31609081" 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>Behr Syndrome</em></strong></p><p>
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In 2 sibs with Behr syndrome (BEHRS; <a href="/entry/210000">210000</a>), <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> identified compound heterozygosity for 2 mutations in the OPA1 gene: I382M (<a href="#0018">605290.0018</a>) and a 4-bp deletion (<a href="#0003">605290.0003</a>). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> concluded that the missense mutation may be a mild mutation and shows strong additive effects when combined with a second mutation. The more severe phenotype in the children was consistent with autosomal recessive or semidominant inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21636302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with Behr syndrome, <a href="#10" class="mim-tip-reference" title="Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P. <strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong> Brain 137: e301, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>] [<a href="https://doi.org/10.1093/brain/awu184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25012220">Bonneau et al. (2014)</a> identified compound heterozygosity for the I382M substitution in the OPA1 gene on 1 allele and different mutations on the other (see, e.g., <a href="#0020">605290.0020</a>). A fourth patient was compound heterozygous for 2 different mutations (<a href="#0003">605290.0003</a> and <a href="#0021">605290.0021</a>). There was no evidence that any of the parents who were heterozygous carriers of the I382M substitution had optic atrophy, but DNA was not available from all asymptomatic parents. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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>Mitochondrial DNA Depletion Syndrome 14</em></strong></p><p>
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In 2 sisters, born of consanguineous Arab parents, with mitochondrial DNA depletion syndrome-14 (MTDPS14; <a href="/entry/616896">616896</a>) resulting in fatal infantile cardioencephalomyopathy, <a href="#45" class="mim-tip-reference" title="Spiegel, R., Saada, A., Flannery, P. J., Burte, F., Soiferman, D., Khayat, M., Eisner, V., Vladovski, E., Taylor, R. W., Bindoff, L. A., Shaag, A., Mandel, H., Schuler-Furman, O., Shalev, S. A., Elpeleg, O., Yu-Wai-Man, P. <strong>Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation.</strong> J. Med. Genet. 53: 127-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26561570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26561570</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26561570">Spiegel et al. (2016)</a> identified a homozygous missense mutation in the OPA1 gene (L534R; <a href="#0023">605290.0023</a>). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26561570" 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>Normal Tension Glaucoma</em></strong></p><p>
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Normal tension glaucoma (NTG; <a href="/entry/606657">606657</a>) is an important subtype of primary open angle glaucoma, in which the intraocular pressure (IOP) is consistently within the statistically normal population range. <a href="#7" class="mim-tip-reference" title="Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S. <strong>A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.</strong> Hum. Genet. 110: 52-56, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810296</a>] [<a href="https://doi.org/10.1007/s00439-001-0645-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810296">Aung et al. (2002)</a> screened 83 well-characterized NTG patients for mutations in the OPA1 gene by heteroduplex analysis and bidirectional sequencing. In this and a second cohort of 80 NTG patients, they found that a single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8, IVS8+4C/T, was strongly associated with the occurrence of NTG. A second SNP, IVS8+32T/C, appeared to be associated with disease in the first cohort, but this finding could not be replicated in a second cohort. In the combined cohort, the compound at-risk genotype IVS8+4C/T,+32T/C (<a href="#0010">605290.0010</a>) was strongly associated with the occurrence of NTG (P = 0.00001 after correcting for testing of 4 genotypes). These results indicated that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11810296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Among 104 patients from 45 families with 33 different OPA1 mutations, <a href="#52" class="mim-tip-reference" title="Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others. <strong>Multi-system neurological disease is common in patients with OPA1 mutations.</strong> Brain 133: 771-786, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20157015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20157015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20157015[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/awq007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20157015">Yu-Wai-Man et al. (2010)</a> found that multisystem neurologic disease involving optic atrophy, deafness, and neuromuscular complications (<a href="/entry/125250">125250</a>) was associated with all types of mutations; however, there was an increased risk with missense mutations (odds ratio (OR) of 3.06, p = 0.0027) and with mutations located within the GTPase region (OR of 2.29, p = 0.0271). Skeletal muscle biopsies from those with extraocular neurologic features showed higher levels of cytochrome c oxidase-deficient fibers and mitochondrial DNA deletions compared to those with pure optic neuropathy, suggesting a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20157015" 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>To analyze the influence of OPA1 gene mutations on optic nerve head morphology in patients with dominant optic atrophy, <a href="#9" class="mim-tip-reference" title="Barboni, P., Carbonelli, M., Savini, G., Foscarini. B., Parisi, V., Valentino, M. L., Carta, A., De Negri, A., Sadun, F., Zeviani, M., Sadun, A. A., Schimpf, S., Wissinger, B., Carelli, V. <strong>OPA1 mutations associated with dominant optic atrophy influence optic nerve head size.</strong> Ophthalmology 117: 1547-1553, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20417568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20417568</a>] [<a href="https://doi.org/10.1016/j.ophtha.2009.12.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20417568">Barboni et al. (2010)</a> studied the optic nerve head of 28 OPA1 mutation-positive patients from 11 pedigrees and 56 age-matched controls by optical coherence tomography (OCT). Patients showed a significantly smaller optic disc area (P less than 0.0001), and vertical (P = 0.018), and horizontal (P less than 0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal optic nerve head area with 2 mutations, whereas a missense mutation linked to a 'dominant optic atrophy plus' phenotype (<a href="#0017">605290.0017</a>) had the smallest ONH measurements. <a href="#9" class="mim-tip-reference" title="Barboni, P., Carbonelli, M., Savini, G., Foscarini. B., Parisi, V., Valentino, M. L., Carta, A., De Negri, A., Sadun, F., Zeviani, M., Sadun, A. A., Schimpf, S., Wissinger, B., Carelli, V. <strong>OPA1 mutations associated with dominant optic atrophy influence optic nerve head size.</strong> Ophthalmology 117: 1547-1553, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20417568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20417568</a>] [<a href="https://doi.org/10.1016/j.ophtha.2009.12.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20417568">Barboni et al. (2010)</a> concluded that their observations suggested a theretofore unrecognized role for OPA1 in eye development, and in particular in modeling optic nerve head size and conformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20417568" 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="#14" class="mim-tip-reference" title="Davies, V. J., Hollins, A. J., Piechota, M. J., Yip, W., Davies, J. R., White, K. E., Nicols, P. P., Boulton, M. E., Votruba, M. <strong>Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function.</strong> Hum. Molec. Genet. 16: 1307-1318, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17428816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17428816</a>] [<a href="https://doi.org/10.1093/hmg/ddm079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17428816">Davies et al. (2007)</a> generated mutant mice carrying an ethylnitrosourea (ENU)-induced Q285X mutation in the Opa1 gene, resulting in a truncated protein. Western analysis showed that the mutation resulted in approximately 50% reduction in Opa1 protein in retina and all tissues. The homozygous mutation was embryonic lethal by 13.5 days postcoitum. Fibroblasts from adult heterozygotes showed an increase in mitochondrial fission and fragmentation. In addition, electron microscopy revealed the slow onset of optic nerve degeneration; reduced visual function in heterozygotes was demonstrated by optokinetic drum testing and the circadian running wheel. <a href="#14" class="mim-tip-reference" title="Davies, V. J., Hollins, A. J., Piechota, M. J., Yip, W., Davies, J. R., White, K. E., Nicols, P. P., Boulton, M. E., Votruba, M. <strong>Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function.</strong> Hum. Molec. Genet. 16: 1307-1318, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17428816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17428816</a>] [<a href="https://doi.org/10.1093/hmg/ddm079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17428816">Davies et al. (2007)</a> concluded that the OPA1 GTPase contains crucial information required for the survival of retinal ganglion cells and that OPA1 is essential for early embryonic survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17428816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605290[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In affected members of one family with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> found an 899G-A transition in exon 9 of the OPA1 gene that changed glycine to glutamic acid at codon 300. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> found a G-to-A transition in the last nucleotide of intron 9 of the OPA1 gene that abolished the acceptor splice site. This mutation results in either skipping of exon 10 with no frameshift in the following exon 11, or a frameshift with a premature stop at the first codon of exon 10 (329) if the newly ectopic acceptor splice site 1 bp downstream of the original is functional. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017079" 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">rs80356530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356530;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=rs80356530" 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=rs80356530" 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=RCV000005387 OR RCV000081763 OR RCV000210745 OR RCV000508703 OR RCV001073751 OR RCV001542739 OR RCV002490322 OR RCV003319160 OR RCV004532291 OR RCV004584316 OR RCV004798716 OR RCV004814831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005387, RCV000081763, RCV000210745, RCV000508703, RCV001073751, RCV001542739, RCV002490322, RCV003319160, RCV004532291, RCV004584316, RCV004798716, RCV004814831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005387...</a>
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<p>In 3 families, <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> found that members with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>) had a 4-bp deletion in exon 27 of the OPA1 gene, 2708delTTAG, that caused 2 amino acid substitutions (val903 to gly, arg904 to asp) and a premature stop at codon 905. This mutation was present in an asymptomatic carrier in one family but was fully penetrant in the other 2 families. This penetrance was expected since minimally affected patients and asymptomatic carriers (with no detectable optic atrophy on fundus examination) had been described. The 3 families were apparently unrelated, but all originated from the northern French provinces and Belgium. Founder effect had been demonstrated by haplotype studies in the British Isles (<a href="#50" class="mim-tip-reference" title="Votruba, M., Moore, A. T., Bhattacharya, S. S. <strong>Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.</strong> Hum. Genet. 102: 79-86, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490303</a>] [<a href="https://doi.org/10.1007/s004390050657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490303">Votruba et al., 1998</a>; <a href="#24" class="mim-tip-reference" title="Johnston, R. L., Seller, M. J., Behnam, J. T., Burdon, M. A., Spalton, D. J. <strong>Dominant optic atrophy: refining the clinical diagnostic criteria in light of genetic linkage studies.</strong> Ophthalmology 106: 123-128, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9917792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9917792</a>] [<a href="https://doi.org/10.1016/S0161-6420(99)90013-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9917792">Johnston et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9490303+11017079+9917792" 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="#48" class="mim-tip-reference" title="Toomes, C., Marchbank, N. J., Mackey, D. A., Craig, J. E., Newbury-Ecob, R. A., Bennett, C. P., Vize, C. J., Desai, S. P., Black, G. C. M., Patel, N., Teimory, M., Markham, A. F., Inglehearn, C. F., Churchill, A. J. <strong>Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.</strong> Hum. Molec. Genet. 10: 1369-1378, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440989</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440989">Toomes et al. (2001)</a> haplotyped 8 unrelated individuals with the 2708delTTAG mutation and concluded that this may be a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. A recalculation of the penetrance of this disorder within 2 of 8 families indicated figures as low as 43% and 62% associated with the 2708delTTAG mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440989" 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 sibs with clinical features of Behr syndrome (BEHRS; <a href="/entry/210000">210000</a>), <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> identified compound heterozygosity for 2 mutations in the OPA1 gene: 2708delTTAG and I382M (<a href="#0018">605290.0018</a>). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> considered the more severe phenotype in the children to be consistent with semidominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21636302" 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 11-year-old girl with Behr syndrome, <a href="#10" class="mim-tip-reference" title="Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P. <strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong> Brain 137: e301, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>] [<a href="https://doi.org/10.1093/brain/awu184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25012220">Bonneau et al. (2014)</a> identified compound heterozygous mutations in the OPA1 gene: a 4-bp deletion (c.2708_2711) in exon 27, resulting in a frameshift and premature termination (Val903GlyfsTer), and a c.1204G-A transition in exon 12, resulting in a val402-to-met (V402M; <a href="#0021">605290.0021</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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">rs879255560 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255560;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=rs879255560" 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=rs879255560" 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=RCV000005388 OR RCV000355298 OR RCV004814832" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005388, RCV000355298, RCV004814832" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005388...</a>
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<p>In affected members of a family with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#16" class="mim-tip-reference" title="Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P. <strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong> Nature Genet. 26: 207-210, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017079</a>] [<a href="https://doi.org/10.1038/79936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017079">Delettre et al. (2000)</a> found a 4-bp deletion in exon 28 of the OPA1 gene (2823delAGTT) that caused a delayed stop, downstream of the original one, resulting in the replacement of the last 19 amino acids of the protein with 24 novel amino acids at the carboxy terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017079" 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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OPA1, ARG290GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908375 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908375;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=rs121908375" 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=rs121908375" 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=RCV000005389 OR RCV000790668 OR RCV001336297 OR RCV004814833" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005389, RCV000790668, RCV001336297, RCV004814833" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005389...</a>
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<p>In a family from Cuba, <a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> demonstrated that members with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>) had a G-to-A transition of nucleotide 869 in exon 8 of the OPA1 gene, predicting an arg290-to-gln amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" 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">rs104893752 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893752;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=rs104893752" 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=rs104893752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893753 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893753;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=rs104893753" 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=rs104893753" 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=RCV000005390 OR RCV000790742 OR RCV003225922 OR RCV004814834" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005390, RCV000790742, RCV003225922, RCV004814834" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005390...</a>
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<p>In a German family, <a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> found that individuals with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>) had a C-to-T transition of nucleotide 1096 in exon 11 of the OPA1 gene, predicted to cause an arg366-to-ter change in the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" 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 OPTIC ATROPHY 1</strong>
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OPA1, 3-BP DEL, 1296CAT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255511 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255511;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=rs879255511" 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=rs879255511" 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=RCV000005391" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005391" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005391</a>
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<p>In affected members of a U.K. family with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> found a 3-bp deletion, del1296CAT, in exon 13 of the OPA1 gene resulting in deletion of the amino acid isoleucine-432. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<strong>.0008 OPTIC ATROPHY 1</strong>
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OPA1, 1-BP DEL, 1354G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255512;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=rs879255512" 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=rs879255512" 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=RCV000005392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005392</a>
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<p>In a second German family with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#1" class="mim-tip-reference" title="Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B. <strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong> Nature Genet. 26: 211-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>] [<a href="https://doi.org/10.1038/79944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017080">Alexander et al. (2000)</a> found that affected members had a 1-bp deletion in the OPA1 gene, 1354delG, causing a frameshift followed by 14 novel amino acids before termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" 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">rs80356531 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356531;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=rs80356531" 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=rs80356531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The prevalence of Kjer type optic atrophy (<a href="/entry/165500">165500</a>) is reported to be highest in Denmark of any geographic area, suggesting a founder effect. In a sample of 33 apparently unrelated Danish families, <a href="#47" class="mim-tip-reference" title="Thiselton, D. L., Alexander, C., Morris, A., Brooks, S., Rosenberg, T., Eiberg, H., Kjer, B., Kjer, P., Bhattacharya, S. S., Votruba, M. <strong>A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.</strong> Hum. Genet. 109: 498-502, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11735024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11735024</a>] [<a href="https://doi.org/10.1007/s004390100600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11735024">Thiselton et al. (2001)</a> screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. In 14 pedigrees, a novel identical mutation in exon 28, 2826delT, was associated with dominant optic atrophy and led to a frameshift and an abnormal C terminus of the OPA1 protein. Haplotype analysis revealed a common haplotype shared by all 14 patients; this haplotype was markedly overrepresented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with dominant optic atrophy over approximately 600 kb encompassing the disease mutation. The authors concluded that a founder mutation is responsible for approximately 42% of the families studied and suggested that presymptomatic screening for the 2826delT mutation may facilitate diagnosis and genetic counseling. The disorder is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11735024" 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> rs10451941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10451941;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/rs10451941?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=rs10451941" 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=rs10451941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs166850 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs166850;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/rs166850?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=rs166850" 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=rs166850" 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=RCV000005394 OR RCV000081772 OR RCV001711248" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005394, RCV000081772, RCV001711248" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005394...</a>
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<p><a href="#7" class="mim-tip-reference" title="Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S. <strong>A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.</strong> Hum. Genet. 110: 52-56, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810296</a>] [<a href="https://doi.org/10.1007/s00439-001-0645-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810296">Aung et al. (2002)</a> found a strong association of normal tension glaucoma (NTG; <a href="/entry/606657">606657</a>) with the T allele at the IVS8+4C/T SNP in combination with the C allele at the IVS8+32T/C SNP of the OPA1 gene in Caucasians. In a second publication, <a href="#6" class="mim-tip-reference" title="Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Brice, G., Child, A. H., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S. <strong>Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma.</strong> Hum. Genet. 110: 513-514, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12073024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12073024</a>] [<a href="https://doi.org/10.1007/s00439-002-0711-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12073024">Aung et al. (2002)</a> found no significant association of this double polymorphism of intron 8 of the OPA1 gene in high-tension primary open angle glaucoma, suggesting a fundamental difference between the 2 forms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12073024+11810296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Mabuchi, F., Tang, S. A., Kashiwagi, K., Yamagata, Z., Iijima, H., Tsukahara, S. <strong>The OPA1 gene polymorphism is associated with normal tension and high tension glaucoma.</strong> Am. J. Ophthal. 143: 125-130, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17188046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17188046</a>] [<a href="https://doi.org/10.1016/j.ajo.2006.09.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17188046">Mabuchi et al. (2007)</a> found a significant association of NTG with the IVS8+32C-T SNP, but not with the IVS8+4C-T SNP, in Japanese. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17188046" 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 137 patients with primary open angle glaucoma (POAG), including 67 with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from the northeast of England, <a href="#54" class="mim-tip-reference" title="Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F. <strong>OPA1 increases the risk of normal but not high tension glaucoma.</strong> J. Med. Genet. 47: 120-125, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19581274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19581274</a>] [<a href="https://doi.org/10.1136/jmg.2009.067512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19581274">Yu-Wai-Man et al. (2010)</a> found significant association between the T allele at IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004) but not HTG. Logistic regression analysis confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (odds ratio, 29.75; p = 0.001). <a href="#54" class="mim-tip-reference" title="Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F. <strong>OPA1 increases the risk of normal but not high tension glaucoma.</strong> J. Med. Genet. 47: 120-125, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19581274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19581274</a>] [<a href="https://doi.org/10.1136/jmg.2009.067512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19581274">Yu-Wai-Man et al. (2010)</a> concluded that the CT/TT compound genotype in intron 8 of the OPA1 gene is a strong genetic risk determinant for NTG but not HTG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19581274" 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">rs80356529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356529;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=rs80356529" 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=rs80356529" 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=RCV000005396 OR RCV000081749 OR RCV000508953 OR RCV003137493 OR RCV003492285 OR RCV004585987 OR RCV004814835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005396, RCV000081749, RCV000508953, RCV003137493, RCV003492285, RCV004585987, RCV004814835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005396...</a>
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<p>In a Japanese patient with optic atrophy and moderate sensorineural deafness (<a href="/entry/125250">125250</a>), <a href="#44" class="mim-tip-reference" title="Shimizu, S., Mori, N., Kishi, M., Sugata, H., Tsuda, A., Kubota, N. <strong>A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy.</strong> Am. J. Ophthal. 135: 256-257, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566046</a>] [<a href="https://doi.org/10.1016/s0002-9394(02)01929-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566046">Shimizu et al. (2003)</a> identified a heterozygous G-to-A transition in the second nucleotide at codon 445 in the OPA1 gene, resulting in an arg445-to-his (R445H) substitution in the GTPase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566046" 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="#37" class="mim-tip-reference" title="Payne, M., Yang, Z., Katz, B. J., Warner, J. E. A., Weight, C. J., Zhao, Y., Pearson, E. D., Treft, R. L., Hillman, T., Kennedy, R. J., Meire, F. M., Zhang, K. <strong>Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1.</strong> Am. J. Ophthal. 138: 749-755, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531309</a>] [<a href="https://doi.org/10.1016/j.ajo.2004.06.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531309">Payne et al. (2004)</a> found this mutation in a large Utah family and an unrelated Belgian family, previously described by <a href="#49" class="mim-tip-reference" title="Treft, R. L., Sanborn, G. E., Carey, J., Swartz, M., Crisp, D., Wester, D. C., Creel, D. <strong>Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy: a new syndrome.</strong> Ophthalmology 91: 908-915, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6493699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6493699</a>] [<a href="https://doi.org/10.1016/s0161-6420(84)34214-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6493699">Treft et al. (1984)</a> and <a href="#31" class="mim-tip-reference" title="Meire, F., De Laey, J. J., de Bie, S., van Staey, M., Matton, M. T. <strong>Dominant optic nerve atrophy with progressive hearing loss and chronic progressive external ophthalmoplegia (CPEO).</strong> Ophthalmic Paediat. Genet. 5: 91-97, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4058877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4058877</a>] [<a href="https://doi.org/10.3109/13816818509007861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4058877">Meire et al. (1985)</a>, respectively. Both families had optic atrophy, deafness, and ophthalmoplegia. The authors hypothesized that, although OPA1 is a nuclear gene, the localization of its gene product to mitochondria suggests that mitochondrial dysfunction might be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15531309+6493699+4058877" 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 third family with optic atrophy and hearing loss, unrelated to the Utah or Belgian families, <a href="#27" class="mim-tip-reference" title="Li, C., Kosmorsky, G., Zhang, K., Katz, B. J., Ge, J., Traboulsi, E. I. <strong>Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation.</strong> Am. J. Med. Genet. 138A: 208-211, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16158427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16158427</a>] [<a href="https://doi.org/10.1002/ajmg.a.30794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16158427">Li et al. (2005)</a> identified the R445H mutation. <a href="#27" class="mim-tip-reference" title="Li, C., Kosmorsky, G., Zhang, K., Katz, B. J., Ge, J., Traboulsi, E. I. <strong>Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation.</strong> Am. J. Med. Genet. 138A: 208-211, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16158427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16158427</a>] [<a href="https://doi.org/10.1002/ajmg.a.30794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16158427">Li et al. (2005)</a> noted that affected members of this family did not have extraocular motility abnormalities or ptosis, thus illustrating the intra- and interfamilial phenotype variability associated with this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16158427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P. <strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong> Ann. Neurol. 58: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240368</a>] [<a href="https://doi.org/10.1002/ana.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240368">Amati-Bonneau et al. (2005)</a> identified the R445H mutation in 5 unrelated patients from 4 families with optic atrophy and deafness, thus confirming that this mutation is specifically associated with hearing loss. One of the patients had been previously reported by <a href="#3" class="mim-tip-reference" title="Amati-Bonneau, P., Odent, S., Derrien, C., Pasquier, L., Malthiery, Y., Reynier, P., Bonneau, D. <strong>The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene.</strong> Am. J. Ophthal. 136: 1170-1171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14644237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14644237</a>] [<a href="https://doi.org/10.1016/s0002-9394(03)00665-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14644237">Amati-Bonneau et al. (2003)</a>. In the Spanish mother and daughter previously reported by <a href="#2" class="mim-tip-reference" title="Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P. <strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong> Ann. Neurol. 58: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240368</a>] [<a href="https://doi.org/10.1002/ana.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240368">Amati-Bonneau et al. (2005)</a>, <a href="#4" class="mim-tip-reference" title="Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others. <strong>OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.</strong> Brain 131: 338-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158317</a>] [<a href="https://doi.org/10.1093/brain/awm298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158317">Amati-Bonneau et al. (2008)</a> noted that the mother had additional features including myopathy, neuropathy, and progressive external ophthalmoplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16240368+18158317+14644237" 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="#46" class="mim-tip-reference" title="Stewart, J. D., Hudson, G., Yu-Wai-Man, P., Blakeley, E. L., He, L., Horvath, R., Maddison, P., Wright, A., Griffiths, P. G., Turnbull, D. M., Taylor, R. W., Chinnery, P. F. <strong>OPA1 in multiple mitochondrial DNA deletion disorders.</strong> Neurology 71: 1829-1831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19029523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19029523</a>] [<a href="https://doi.org/10.1212/01.wnl.0000335931.54095.0a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19029523">Stewart et al. (2008)</a> identified the R445H mutation in 2 probands with optic atrophy and myopathy associated with mitochondrial DNA deletions. One proband also had deafness. The other proband did not have hearing loss, but 3 affected family members had hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19029523" 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 27-year-old Italian woman and her 57-year-old mother with DOA+, <a href="#34" class="mim-tip-reference" title="Napolitano, F., Terracciano, C., Bruno, G., Nesti, C., Barillari, M. R., Barillari, U., Santorelli, F. M., Melone, M. A. B., Esposito, T., Sampaolo, S. <strong>Intrafamilial 'DOA-plus' phenotype variability related to different OMI/HTRA2 expression.</strong> Am. J. Med. Genet. 182A: 176-182, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31609081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31609081</a>] [<a href="https://doi.org/10.1002/ajmg.a.61381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31609081">Napolitano et al. (2020)</a> identified heterozygosity for the mutation in the OPA1 gene (R445H; <a href="#0011">605290.0011</a>). The mutation was identified by Sanger sequencing of the OPA1 gene. The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (<a href="/entry/606441">606441</a>) was increased in the muscle tissue of both patients, although more so in the daughter. <a href="#34" class="mim-tip-reference" title="Napolitano, F., Terracciano, C., Bruno, G., Nesti, C., Barillari, M. R., Barillari, U., Santorelli, F. M., Melone, M. A. B., Esposito, T., Sampaolo, S. <strong>Intrafamilial 'DOA-plus' phenotype variability related to different OMI/HTRA2 expression.</strong> Am. J. Med. Genet. 182A: 176-182, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31609081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31609081</a>] [<a href="https://doi.org/10.1002/ajmg.a.61381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31609081">Napolitano et al. (2020)</a> hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31609081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Chinese family in which 9 members had autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), accompanied in some by high frequency hearing loss (<a href="/entry/125250">125250</a>) and/or myopia, <a href="#12" class="mim-tip-reference" title="Chen, S., Zhang, Y., Wang, Y., Li, W., Huang, S., Chu, X., Wang, L., Zhang, M., Liu, Z. <strong>A novel OPA1 mutation responsible for autosomal dominant optic atrophy with high frequency hearing loss in a Chinese family.</strong> Am. J. Ophthal. 143: 186-188, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17188070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17188070</a>] [<a href="https://doi.org/10.1016/j.ajo.2006.06.049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17188070">Chen et al. (2007)</a> identified a 2-bp deletion in exon 28 of the OPA1 gene (2848_2849delGA), which resulted in a premature stop at codon 953 and a loss of the last 11 amino acids of the protein, in all affected members. The mutation was absent in a family member with myopia alone as well as in all unaffected family members and 100 normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17188070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with progressive external ophthalmoplegia, visual loss, hearing loss, and mild myopathy and ataxia (<a href="/entry/125250">125250</a>), <a href="#18" class="mim-tip-reference" title="Ferraris, S., Clark, S., Garelli, E., Davidzon, G., Moore, S. A., Kardon, R. H., Bienstock, R. J., Longley, M. J., Mancuso, M., Rios, P. G., Hirano, M., Copeland, W. C., DiMauro, S. <strong>Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.</strong> Arch. Neurol. 65: 125-131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195150[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/10.1001/archneurol.2007.9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195150">Ferraris et al. (2008)</a> identified a heterozygous 1741A-G transition in the OPA1 gene, resulting in a tyr582-to-cys (Y582C) substitution. The patient was also found to carry a gly416-to-ala (G416A) variant in the POLG2 gene (<a href="/entry/604983">604983</a>), but in vitro functional studies showed no functional deficits of the POLG2 variant. <a href="#18" class="mim-tip-reference" title="Ferraris, S., Clark, S., Garelli, E., Davidzon, G., Moore, S. A., Kardon, R. H., Bienstock, R. J., Longley, M. J., Mancuso, M., Rios, P. G., Hirano, M., Copeland, W. C., DiMauro, S. <strong>Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.</strong> Arch. Neurol. 65: 125-131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195150[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/10.1001/archneurol.2007.9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195150">Ferraris et al. (2008)</a> concluded that the OPA1 mutation was responsible for the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195150" 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 WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</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">rs387906899 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906899;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=rs387906899" 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=rs387906899" 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=RCV000023414 OR RCV000508763 OR RCV004786281" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023414, RCV000508763, RCV004786281" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023414...</a>
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<p>In a brother and sister with optic atrophy, progressive external ophthalmoplegia, myopathy, ataxia, but no hearing loss (<a href="/entry/125250">125250</a>), <a href="#46" class="mim-tip-reference" title="Stewart, J. D., Hudson, G., Yu-Wai-Man, P., Blakeley, E. L., He, L., Horvath, R., Maddison, P., Wright, A., Griffiths, P. G., Turnbull, D. M., Taylor, R. W., Chinnery, P. F. <strong>OPA1 in multiple mitochondrial DNA deletion disorders.</strong> Neurology 71: 1829-1831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19029523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19029523</a>] [<a href="https://doi.org/10.1212/01.wnl.0000335931.54095.0a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19029523">Stewart et al. (2008)</a> identified heterozygosity for a 1294A-G transition in the OPA1 gene, resulting in an ile432-to-val (I432V) substitution in the GTPase domain. The mutation was not detected in 344 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19029523" 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>.0015 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
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OPA1, SER545ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398124298 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398124298;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=rs398124298" 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=rs398124298" 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=RCV000023415 OR RCV000508898 OR RCV001659726 OR RCV002464072 OR RCV004814921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023415, RCV000508898, RCV001659726, RCV002464072, RCV004814921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023415...</a>
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<p>In 7 affected members of a 3-generation family with optic atrophy, ataxia, and progressive external ophthalmoplegia (<a href="/entry/125250">125250</a>), <a href="#22" class="mim-tip-reference" title="Hudson, G., Amati-Bonneau, P., Blakely, E. L., Stewart, J. D., He, L., Schaefer, A. M., Griffiths, P. G., Ahlqvist, K., Suomalainen, A., Reynier, P., McFarland, R., Turnbull, D. M., Chinnery, P. F., Taylor, R. W. <strong>Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness, and multiple mitochondrial deletions: a novel disorder of mtDNA maintenance.</strong> Brain 131: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18065439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18065439</a>] [<a href="https://doi.org/10.1093/brain/awm272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18065439">Hudson et al. (2008)</a> identified heterozygosity for a 1635C-G transversion in exon 17 of the OPA1 gene, resulting in a ser545-to-arg (S545R) substitution in the GTPase domain. Three patients had deafness with onset in the third or fourth decade, and 3 patients had neuropathy and myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18065439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of an Austrian family with optic atrophy, deafness, progressive external ophthalmoplegia, ataxia, and neuropathy (<a href="/entry/125250">125250</a>), <a href="#52" class="mim-tip-reference" title="Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others. <strong>Multi-system neurological disease is common in patients with OPA1 mutations.</strong> Brain 133: 771-786, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20157015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20157015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20157015[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/awq007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20157015">Yu-Wai-Man et al. (2010)</a> identified a heterozygous S545R mutation, which they noted was in the dynamin domain of the protein. Two patients in their thirties had deafness, whereas an older family member in her sixties did not have deafness. The authors also identified the S545R mutation in a 30-year-old French man with optic atrophy, deafness, ataxia, myopathy, and neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20157015" 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>.0016 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</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">rs387906900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906900;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=rs387906900" 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=rs387906900" 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=RCV000023416 OR RCV001857360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023416, RCV001857360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023416...</a>
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<p>In an Italian man with optic atrophy, deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (<a href="/entry/125250">125250</a>), <a href="#4" class="mim-tip-reference" title="Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others. <strong>OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.</strong> Brain 131: 338-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158317</a>] [<a href="https://doi.org/10.1093/brain/awm298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158317">Amati-Bonneau et al. (2008)</a> identified a heterozygous 1316G-T transversion in exon 14 of the OPA1 gene, resulting in a gly439-to-val (G439V) substitution in the GTPase domain. His 7-year-old daughter also carried the G439V mutation and had optic atrophy and deafness. The mutation was not identified in 460 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18158317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
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OPA1, VAL910ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906901 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906901;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=rs387906901" 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=rs387906901" 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=RCV000023417" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023417" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023417</a>
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<p>In an Italian man with optic atrophy, deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (<a href="/entry/125250">125250</a>), <a href="#4" class="mim-tip-reference" title="Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others. <strong>OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.</strong> Brain 131: 338-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158317</a>] [<a href="https://doi.org/10.1093/brain/awm298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158317">Amati-Bonneau et al. (2008)</a> identified a 2729T-A transversion in exon 27 of the OPA1 gene, resulting in a val910-to-asp substitution (V910D). At least 6 other members of the family were affected. This mutation resides outside the GTPase domain, at the interface of the 2 effector domains performing the conformational change, and was associated with a milder phenotype than that of other families included in the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18158317" 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> rs143319805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs143319805;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/rs143319805?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=rs143319805" 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=rs143319805" 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=RCV000043607 OR RCV000081747 OR RCV000210748 OR RCV000677258 OR RCV001249638 OR RCV001267306 OR RCV003993775 OR RCV004537182 OR RCV004814984" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043607, RCV000081747, RCV000210748, RCV000677258, RCV001249638, RCV001267306, RCV003993775, RCV004537182, RCV004814984" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043607...</a>
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<p>In a patient with autosomal dominant optic atrophy (<a href="/entry/165500">165500</a>), <a href="#42" class="mim-tip-reference" title="Schimpf, S., Fuhrmann, N., Schaich, S., Wissinger, B. <strong>Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons.</strong> Hum. Mutat. 29: 106-112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722006</a>] [<a href="https://doi.org/10.1002/humu.20607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722006">Schimpf et al. (2008)</a> identified a heterozygous 1146A-G transition in the OPA1 gene, resulting in an ile382-to-met (I382M) substitution at a conserved residue in the GTPase domain. The mutation was not found in 100 controls. No clinical information was provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17722006" 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 sibs with Behr syndrome (BEHRS; <a href="/entry/210000">210000</a>), <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> identified compound heterozygosity for 2 mutations in the OPA1 gene: I382M and a 4-bp deletion (<a href="#0003">605290.0003</a>). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. <a href="#41" class="mim-tip-reference" title="Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., Scaglia, F. <strong>Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.</strong> Molec. Genet. Metab. 103: 383-387, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636302</a>] [<a href="https://doi.org/10.1016/j.ymgme.2011.04.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636302">Schaaf et al. (2011)</a> concluded that the missense mutation may be a mild mutation and shows strong additive effects when combined with a second mutation. The more severe phenotype in the children was consistent with autosomal recessive or semidominant inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21636302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with Behr syndrome, <a href="#10" class="mim-tip-reference" title="Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P. <strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong> Brain 137: e301, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>] [<a href="https://doi.org/10.1093/brain/awu184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25012220">Bonneau et al. (2014)</a> identified compound heterozygous mutations in the OPA1 gene: each patient carried the I382M substitution in exon 12 on 1 allele and a different mutation on the other allele (see, e.g., <a href="#0020">605290.0020</a>). There was no evidence that any of the parents who were heterozygous carriers of the I382M substitution had optic atrophy, but DNA was not available from all asymptomatic parents. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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>.0019 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</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">rs879255592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255592;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=rs879255592" 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=rs879255592" 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=RCV000210742" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210742" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210742</a>
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<p>In 2 adult brothers with optic atrophy without deafness, but with ataxia, neuropathy, and spasticity (<a href="/entry/125250">125250</a>), <a href="#29" class="mim-tip-reference" title="Marelli, C., Amati-Bonneau, P., Reynier, P., Layet, V., Layet, A., Stevanin, G., Brissaud, E., Bonneau, D., Durr, A., Brice, A. <strong>Heterozygous OPA1 mutations in Behr syndrome.</strong> Brain 134: e169, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21112924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21112924</a>] [<a href="https://doi.org/10.1093/brain/awq306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21112924">Marelli et al. (2011)</a> identified a heterozygous c.1652G-A transition in exon 17 of the OPA1 gene, resulting in a cys551-to-tyr (C551Y) substitution at a highly conserved residue in the dynamin domain. Their asymptomatic mother did not carry the mutation; DNA from the apparently unaffected father was not available. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21112924" 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">rs879255593 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255593;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=rs879255593" 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=rs879255593" 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 14-year-old boy with Behr syndrome (BEHRS; <a href="/entry/210000">210000</a>), <a href="#10" class="mim-tip-reference" title="Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P. <strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong> Brain 137: e301, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>] [<a href="https://doi.org/10.1093/brain/awu184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25012220">Bonneau et al. (2014)</a> identified compound heterozygous mutations in the OPA1 gene: a c.2470C-T transition in exon 24, resulting in an arg824-to-ter (R824X) substitution, and a c.1146A-G transition in exon 12, resulting in an ile382-to-met (I382M; <a href="#0018">605290.0018</a>) substitution. The mother, who had mild optic atrophy, carried the R824X mutation; DNA from the asymptomatic father was not available. The patient had mildly delayed psychomotor development, optic atrophy, ataxia, dysmetria, and axonal sensory neuropathy; he required assistance for ambulation after age 8. Brain imaging showed mild cerebellar atrophy and periventricular white matter abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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">rs879255594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255594;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=rs879255594" 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=rs879255594" 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=RCV000210739 OR RCV003556273" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210739, RCV003556273" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210739...</a>
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<p>For discussion of the c.1204G-A transition in exon 12 of the OPA1 gene resulting in a val402-to-met (V402M) substitution that was found in compound heterozygous state in a patient with Behr syndrome (BEHRS; <a href="/entry/210000">210000</a>) by <a href="#10" class="mim-tip-reference" title="Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P. <strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong> Brain 137: e301, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>] [<a href="https://doi.org/10.1093/brain/awu184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25012220">Bonneau et al. (2014)</a>, see <a href="#0003">605290.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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">rs879255595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255595;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=rs879255595" 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=rs879255595" 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 20-year-old Italian man with Behr syndrome (BERHS; <a href="/entry/210000">210000</a>), <a href="#11" class="mim-tip-reference" title="Carelli, V., Sabatelli, M., Carrozzo, R., Rizza, T., Schimpf, S., Wissinger, B., Zanna, C., Rugolo, M., La Morgia, C., Caporali, L., Carbonelli, M., Barboni, P., Tonon, C., Lodi, R., Bertini, E. <strong>'Behr syndrome' with OPA1 compound heterozygote mutations.</strong> Brain 138: e321, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25146916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25146916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25146916[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/awu234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25146916">Carelli et al. (2015)</a> identified compound heterozygous mutations in the OPA1 gene: a G-to-T transversion in intron 17 (c.1705+1G-T), resulting in a splice site mutation, premature termination and functional haploinsufficiency, and I382M (<a href="/entry/605190#0018">605190.0018</a>). The patient's mother and several maternal relatives with isolated optic atrophy were heterozygous for the splice site mutation, but there was also evidence of incomplete penetrance for this mutation. The father, who was heterozygous for the I382M mutation, was clinically unaffected, suggesting that it may be a hypomorphic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25146916" 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>.0023 MITOCHONDRIAL DNA DEPLETION SYNDROME 14 (ENCEPHALOCARDIOMYOPATHIC TYPE) (1 family)</strong>
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OPA1, LEU534ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869312995 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312995;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=rs869312995" 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=rs869312995" 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=RCV000210746" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210746" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210746</a>
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<p>In 2 sisters, born of consanguineous Arab parents, with mitochondrial DNA depletion syndrome-14 (MTDPS14; <a href="/entry/616896">616896</a>), <a href="#45" class="mim-tip-reference" title="Spiegel, R., Saada, A., Flannery, P. J., Burte, F., Soiferman, D., Khayat, M., Eisner, V., Vladovski, E., Taylor, R. W., Bindoff, L. A., Shaag, A., Mandel, H., Schuler-Furman, O., Shalev, S. A., Elpeleg, O., Yu-Wai-Man, P. <strong>Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation.</strong> J. Med. Genet. 53: 127-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26561570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26561570</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26561570">Spiegel et al. (2016)</a> identified a homozygous c.1601T-G transversion (c.1601T-G, NM_015560.2) in the OPA1 gene, resulting in a leu534-to-arg (L534R) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the ExAC database or in 120 ethnically matched controls. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. The patients showed hypotonia, peripheral hypertonia, profound neurodevelopmental delay, optic atrophy, and normal lactate. Both developed progressive hypertrophic cardiomyopathy and died in infancy. Skeletal muscle biopsies showed a global decrease in all mitochondrial respiratory chain activities, with complexes I and IV being the most affected, as well as significant mtDNA depletion, with a 78% decrease compared to controls. Electron microscopy of 1 patient showed large mitochondria with incomplete fusion of the inner mitochondrial membrane. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26561570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Alexander2000" class="mim-anchor"></a>
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Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B.
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<strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong>
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Nature Genet. 26: 211-215, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017080" 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/10.1038/79944" target="_blank">Full Text</a>]
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<a id="Amati-Bonneau2005" class="mim-anchor"></a>
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Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P.
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<strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong>
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Ann. Neurol. 58: 958-963, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240368" 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.20681" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Amati-Bonneau2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Amati-Bonneau, P., Odent, S., Derrien, C., Pasquier, L., Malthiery, Y., Reynier, P., Bonneau, D.
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<strong>The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene.</strong>
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Am. J. Ophthal. 136: 1170-1171, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14644237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14644237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14644237" 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/s0002-9394(03)00665-2" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Amati-Bonneau2008" class="mim-anchor"></a>
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<div class="">
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Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others.
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<strong>OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.</strong>
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Brain 131: 338-351, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158317</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18158317" 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/awm298" target="_blank">Full Text</a>]
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<a id="An2013" class="mim-anchor"></a>
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An, H.-J., Cho, G., Lee, J.-O., Paik, S.-G., Kim, Y. S., Lee, H.
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<strong>Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria.</strong>
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Proc. Nat. Acad. Sci. 110: 13014-12019, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23878241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23878241</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23878241[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=23878241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1307170110" target="_blank">Full Text</a>]
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<a id="Aung2002" class="mim-anchor"></a>
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Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Brice, G., Child, A. H., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S.
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<strong>Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma.</strong>
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Hum. Genet. 110: 513-514, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12073024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12073024</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12073024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0711-9" target="_blank">Full Text</a>]
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<a id="Aung2002" class="mim-anchor"></a>
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<div class="">
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Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S.
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<strong>A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.</strong>
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Hum. Genet. 110: 52-56, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810296</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11810296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-001-0645-7" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Ban2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ban, T., Heymann, J. A. W., Song, Z., Hinshaw, J. E., Chan, D. C.
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<strong>OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.</strong>
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Hum. Molec. Genet. 19: 2113-2122, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185555[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=20185555" 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/ddq088" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Barboni2010" class="mim-anchor"></a>
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<div class="">
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Barboni, P., Carbonelli, M., Savini, G., Foscarini. B., Parisi, V., Valentino, M. L., Carta, A., De Negri, A., Sadun, F., Zeviani, M., Sadun, A. A., Schimpf, S., Wissinger, B., Carelli, V.
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<strong>OPA1 mutations associated with dominant optic atrophy influence optic nerve head size.</strong>
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Ophthalmology 117: 1547-1553, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20417568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20417568</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20417568" 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.ophtha.2009.12.042" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Bonneau2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P.
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<strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong>
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Brain 137: e301, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25012220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25012220</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25012220" 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/awu184" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Carelli2015" class="mim-anchor"></a>
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Carelli, V., Sabatelli, M., Carrozzo, R., Rizza, T., Schimpf, S., Wissinger, B., Zanna, C., Rugolo, M., La Morgia, C., Caporali, L., Carbonelli, M., Barboni, P., Tonon, C., Lodi, R., Bertini, E.
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<strong>'Behr syndrome' with OPA1 compound heterozygote mutations.</strong>
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Brain 138: e321, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25146916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25146916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25146916[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=25146916" 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/awu234" target="_blank">Full Text</a>]
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<a id="Chen2007" class="mim-anchor"></a>
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Chen, S., Zhang, Y., Wang, Y., Li, W., Huang, S., Chu, X., Wang, L., Zhang, M., Liu, Z.
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<strong>A novel OPA1 mutation responsible for autosomal dominant optic atrophy with high frequency hearing loss in a Chinese family.</strong>
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Am. J. Ophthal. 143: 186-188, 2007.
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[<a href="https://doi.org/10.1016/j.ajo.2006.06.049" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0407043101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm079" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-001-0633-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/79936" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gr.108696.110" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2007.9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.06.025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.062570" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.200906083" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awm272" target="_blank">Full Text</a>]
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<a id="Spiegel2016" class="mim-anchor"></a>
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Spiegel, R., Saada, A., Flannery, P. J., Burte, F., Soiferman, D., Khayat, M., Eisner, V., Vladovski, E., Taylor, R. W., Bindoff, L. A., Shaag, A., Mandel, H., Schuler-Furman, O., Shalev, S. A., Elpeleg, O., Yu-Wai-Man, P.
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<strong>Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation.</strong>
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J. Med. Genet. 53: 127-131, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26561570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26561570</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26561570" 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/10.1136/jmedgenet-2015-103361" target="_blank">Full Text</a>]
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<a id="Stewart2008" class="mim-anchor"></a>
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Stewart, J. D., Hudson, G., Yu-Wai-Man, P., Blakeley, E. L., He, L., Horvath, R., Maddison, P., Wright, A., Griffiths, P. G., Turnbull, D. M., Taylor, R. W., Chinnery, P. F.
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<strong>OPA1 in multiple mitochondrial DNA deletion disorders.</strong>
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Neurology 71: 1829-1831, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19029523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19029523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19029523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000335931.54095.0a" target="_blank">Full Text</a>]
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<a id="Thiselton2001" class="mim-anchor"></a>
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Thiselton, D. L., Alexander, C., Morris, A., Brooks, S., Rosenberg, T., Eiberg, H., Kjer, B., Kjer, P., Bhattacharya, S. S., Votruba, M.
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<strong>A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.</strong>
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Hum. Genet. 109: 498-502, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11735024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11735024</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11735024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390100600" target="_blank">Full Text</a>]
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<a id="Toomes2001" class="mim-anchor"></a>
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Toomes, C., Marchbank, N. J., Mackey, D. A., Craig, J. E., Newbury-Ecob, R. A., Bennett, C. P., Vize, C. J., Desai, S. P., Black, G. C. M., Patel, N., Teimory, M., Markham, A. F., Inglehearn, C. F., Churchill, A. J.
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<strong>Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.</strong>
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Hum. Molec. Genet. 10: 1369-1378, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440989" 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/10.13.1369" target="_blank">Full Text</a>]
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<a id="Treft1984" class="mim-anchor"></a>
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Treft, R. L., Sanborn, G. E., Carey, J., Swartz, M., Crisp, D., Wester, D. C., Creel, D.
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<strong>Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy: a new syndrome.</strong>
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Ophthalmology 91: 908-915, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6493699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6493699</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6493699" 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/s0161-6420(84)34214-2" target="_blank">Full Text</a>]
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<a id="50" class="mim-anchor"></a>
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<a id="Votruba1998" class="mim-anchor"></a>
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Votruba, M., Moore, A. T., Bhattacharya, S. S.
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<strong>Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.</strong>
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Hum. Genet. 102: 79-86, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490303</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050657" target="_blank">Full Text</a>]
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<a id="51" class="mim-anchor"></a>
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<a id="Wai2015" class="mim-anchor"></a>
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Wai, T., Garcia-Prieto, J., Baker, M. J., Merkwirth, C., Benit, P., Rustin, P., Ruperez, F. J., Barbas, C., Ibanez, B., Langer, T.
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<strong>Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.</strong>
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Science 350: aad0116, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785494</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26785494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aad0116" target="_blank">Full Text</a>]
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<a id="Yu-Wai-Man2010" class="mim-anchor"></a>
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Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others.
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<strong>Multi-system neurological disease is common in patients with OPA1 mutations.</strong>
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Brain 133: 771-786, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20157015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20157015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20157015[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=20157015" 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/awq007" target="_blank">Full Text</a>]
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<a id="Yu-Wai-Man2010" class="mim-anchor"></a>
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Yu-Wai-Man, P., Sitarz, K. S., Samuels, D. C., Griffiths, P. G., Reeve, A. K., Bindoff, L. A., Horvath, R., Chinnery, P. F.
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<strong>OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules.</strong>
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Hum. Molec. Genet. 19: 3043-3052, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484224[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=20484224" 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/ddq209" target="_blank">Full Text</a>]
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<a id="54" class="mim-anchor"></a>
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<a id="Yu-Wai-Man2010" class="mim-anchor"></a>
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<div class="">
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Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F.
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<strong>OPA1 increases the risk of normal but not high tension glaucoma.</strong>
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J. Med. Genet. 47: 120-125, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19581274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19581274</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19581274" 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/10.1136/jmg.2009.067512" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 10/15/2021
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<span class="mim-text-font">
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Bao Lige - updated : 10/14/2019<br>Patricia A. Hartz - updated : 08/18/2016<br>Cassandra L. Kniffin - updated : 4/5/2016<br>Ada Hamosh - updated : 1/31/2014<br>George E. Tiller - updated : 8/27/2013<br>George E. Tiller - updated : 8/16/2013<br>Cassandra L. Kniffin - updated : 5/22/2013<br>Jane Kelly - updated : 2/17/2012<br>Cassandra L. Kniffin - updated : 5/19/2011<br>Matthew B. Gross - updated : 5/18/2011<br>Patricia A. Hartz - updated : 4/11/2011<br>Marla J. F. O'Neill - updated : 1/20/2011<br>Marla J. F. O'Neill - updated : 8/25/2010<br>Cassandra L. Kniffin - updated : 3/26/2009<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Cassandra L. Kniffin - updated : 1/7/2009<br>Patricia A. Hartz - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 3/4/2008<br>Jane Kelly - updated : 3/30/2007<br>Jane Kelly - updated : 3/23/2007<br>Paul J. Converse - updated : 2/20/2007<br>Cassandra L. Kniffin - updated : 3/27/2006<br>Marla J. F. O'Neill - updated : 10/25/2005<br>Jane Kelly - updated : 6/23/2005<br>Patricia A. Hartz - updated : 4/27/2005<br>Ada Hamosh - updated : 12/29/2004<br>Patricia A. Hartz - updated : 4/28/2003<br>Jane Kelly - updated : 2/14/2003<br>Victor A. McKusick - updated : 6/7/2002<br>Victor A. McKusick - updated : 1/25/2002<br>Victor A. McKusick - updated : 1/2/2002<br>Victor A. McKusick - updated : 12/6/2001<br>George E. Tiller - updated : 11/14/2001
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Victor A. McKusick : 9/26/2000
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carol : 10/15/2021
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alopez : 02/17/2021<br>ckniffin : 08/17/2020<br>carol : 06/16/2020<br>mgross : 10/14/2019<br>carol : 01/02/2018<br>joanna : 08/30/2016<br>alopez : 08/18/2016<br>alopez : 04/07/2016<br>alopez : 4/7/2016<br>ckniffin : 4/5/2016<br>alopez : 1/31/2014<br>carol : 10/14/2013<br>carol : 8/28/2013<br>alopez : 8/28/2013<br>tpirozzi : 8/28/2013<br>tpirozzi : 8/27/2013<br>tpirozzi : 8/27/2013<br>tpirozzi : 8/27/2013<br>tpirozzi : 8/27/2013<br>carol : 8/19/2013<br>tpirozzi : 8/19/2013<br>tpirozzi : 8/19/2013<br>tpirozzi : 8/16/2013<br>tpirozzi : 6/28/2013<br>carol : 6/5/2013<br>ckniffin : 5/22/2013<br>alopez : 2/17/2012<br>wwang : 6/20/2011<br>terry : 6/3/2011<br>ckniffin : 5/19/2011<br>mgross : 5/18/2011<br>mgross : 5/18/2011<br>terry : 4/11/2011<br>wwang : 2/3/2011<br>terry : 1/20/2011<br>terry : 10/13/2010<br>wwang : 8/26/2010<br>terry : 8/25/2010<br>wwang : 4/1/2009<br>ckniffin : 3/26/2009<br>wwang : 3/25/2009<br>ckniffin : 3/16/2009<br>wwang : 1/9/2009<br>ckniffin : 1/7/2009<br>mgross : 3/24/2008<br>wwang : 3/19/2008<br>ckniffin : 3/4/2008<br>terry : 5/11/2007<br>carol : 5/11/2007<br>carol : 3/30/2007<br>carol : 3/23/2007<br>mgross : 2/21/2007<br>mgross : 2/20/2007<br>wwang : 4/6/2006<br>ckniffin : 3/27/2006<br>carol : 3/10/2006<br>ckniffin : 3/10/2006<br>alopez : 12/9/2005<br>carol : 10/25/2005<br>alopez : 6/23/2005<br>wwang : 5/10/2005<br>wwang : 5/2/2005<br>ckniffin : 4/28/2005<br>mgross : 4/27/2005<br>mgross : 4/27/2005<br>alopez : 12/30/2004<br>alopez : 12/30/2004<br>terry : 12/29/2004<br>cwells : 5/5/2003<br>terry : 4/28/2003<br>carol : 2/14/2003<br>alopez : 6/13/2002<br>terry : 6/7/2002<br>carol : 1/30/2002<br>carol : 1/30/2002<br>terry : 1/25/2002<br>carol : 1/16/2002<br>mcapotos : 1/4/2002<br>terry : 1/2/2002<br>carol : 1/2/2002<br>mcapotos : 12/13/2001<br>terry : 12/6/2001<br>alopez : 11/21/2001<br>cwells : 11/20/2001<br>cwells : 11/20/2001<br>cwells : 11/14/2001<br>mcapotos : 3/13/2001<br>carol : 1/4/2001<br>alopez : 9/26/2000
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605290
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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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OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase; OPA1
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</span>
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</h3>
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</div>
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<br />
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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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OPA1 GENE<br />
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KIAA0567<br />
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DYNAMIN-LIKE 120-KD PROTEIN, MITOCHONDRIAL
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</span>
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</h4>
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</div>
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<br />
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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: OPA1</em></strong>
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</span>
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</p>
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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> 715374003, 717336005;
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</p>
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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: 3q29
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:193,593,208-193,697,811 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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3q29
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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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?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)
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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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616896
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Glaucoma, normal tension, susceptibility to}
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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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606657
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Behr syndrome
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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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210000
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Optic atrophy 1
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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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165500
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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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<tr>
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<td>
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<span class="mim-font">
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Optic atrophy plus syndrome
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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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125250
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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>The OPA1 gene encodes a protein that localizes to the inner mitochondrial membrane and regulates several important cellular processes including stability of the mitochondrial network, mitochondrial bioenergetic output, and sequestration of proapoptotic cytochrome c oxidase molecules within the mitochondrial cristae spaces (summary by Yu-Wai-Man et al., 2010). </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 sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned OPA1, which they designated KIAA0567. The deduced protein contained 978 amino acids. RT-PCR detected highest OPA1 expression in heart and kidney, with low expression in all other tissues examined. </p><p>In the fission yeast S. pombe, Pelloquin et al. (1998, 1999) identified a dynamin-related protein, Msp1, essential for the maintenance of mitochondrial DNA, as is true for Mgm1p, its ortholog in S. cerevisiae (Jones and Fangman, 1992). Both proteins have a GTPase and a central dynamin domain conserved among all dynamins and a highly basic N-terminal domain required for mitochondrial localization. Delettre et al. (2000) searched for a human Msp1/Mgm1p homolog in nucleotide databases and identified the KIAA0567 cDNA previously cloned by Nagase et al. (1998). The 960-amino acid protein shared 19% and 17% identity to Msp1 and Mgm1p, respectively. Delettre et al. (2000) then retrieved the sequence of the gene, which they referred to as OPA1, in 2 overlapping clones from the Whitehead Institute server. Labeling studies indicated that Opa1 is a component of the mitochondrial network. Mitochondrial localization of OPA1 was also consistent with a ubiquitous expression of its transcripts in all tissues examined by Northern blot. </p><p>Alexander et al. (2000) established a PAC contig covering the entire optic atrophy-1 (165500) candidate region of approximately 1 Mb. By a sequence skimming approach, they independently identified the the OPA1 gene, encoding a polypeptide with homology to dynamin-related GTPases. </p><p>By RT-PCR of human RNA, Delettre et al. (2001) cloned 8 OPA1 variants resulting from alternative splicing of exons 4, 4b, and 5b. All 8 OPA1 isoforms contain an N-terminal mitochondrial leader sequence, a central coiled-coil region, a GTPase domain, a dynamin central region, and a C-terminal coiled-coil region. Exons 4b and 5b encode 18- and 37-amino acid sequences, respectively. The sequence encoded by exon 5b was predicted to form a coiled-coil. RT-PCR detected variable expression of all 8 OPA1 variants in the 11 tissues tested. In retina, heart, skeletal muscle, lung, ovary, and fetal brain, variants 3/4/5/6 and 3/5/5b/6, in which the numbers indicate the exons present from exon 3 to exon 6, showed highest expression. In kidney, liver, and colon, variant 3/4/5/5b/6 showed highest expression. Except in skeletal muscle, variants 3/4b/5/5b/6 and 3/4/4b/5/6 showed low expression. Variants 3/5/6 and 3/4b/5/6 were weakly expressed in all tissues. </p><p>Olichon et al. (2007) further characterized the 8 OPA1 splice variants. They reported that all 8 OPA1 isoforms have a transmembrane domain immediately following the N-terminal mitochondrial targeting signal. The isoforms differ only in the presence or absence of domains 4, 4b, and 5b, which are encoded by exons 4, 4b, and 5b, respectively, within the region between the transmembrane domain and the central coiled-coil region. Olichon et al. (2007) also presented evidence suggesting that short forms of the OPA1 isoforms are produced by proteolytic processing. Exon-specific qualitative PCR revealed tissue-specific expression of OPA1 variants, with variant 3/4/4b/6 predominating in brain, variant 3/4/5/6 predominating in heart, and variant 3/4/5b/6 predominating in liver, kidney, and thymus. Phylogenetic analysis revealed that exon 4 is conserved throughout evolution, whereas exons 4b and 5b are vertebrate specific. </p><p>Elachouri et al. (2011) stated that the common C-terminal domain found in all OPA1 isoforms contains a GTPase domain and a GTPase effector domain (GED). They also reported that exon 4b encodes a second transmembrane domain. </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>Alexander et al. (2000) stated that the OPA1 gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. </p><p>Delettre et al. (2001) reported that the OPA1 gene contains 31 exons, including the alternatively spliced exons 4, 4b, and 5b. The last exon in noncoding. </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 fluorescence in situ hybridization, Delettre et al. (2000) mapped the OPA1 gene to chromosome 3q28-q29, the region to which the locus for optic atrophy-1 had been mapped. </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>Olichon et al. (2003) determined that the downregulation of OPA1 in HeLa cells with expression of specific small interfering RNA (siRNA) leads to fragmentation of the mitochondrial network, dissipation of the mitochondrial membrane potential, and disorganization of the cristae. These events were followed by cytochrome c (123970) release and caspase (see 600636)-dependent apoptotic nuclear events. In a human ovarian carcinoma cell line, siRNA-induced apoptosis was inhibited by BCL2 (151430) overexpression. Olichon et al. (2003) concluded that OPA1 is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity. As the loss of OPA1 committed cells to apoptosis without any other stimulus, Olichon et al. (2003) proposed that OPA1 is involved in the sequestration of cytochrome c, and that OPA1 may be a target for mitochondrial apoptotic effectors. They also proposed that abnormal apoptosis is a likely process leading to the retinal ganglion cell degeneration in autosomal dominant optic atrophy (165500) patients. </p><p>Meeusen et al. (2004) captured mitochondrial fusion in vitro in transgenic experiments using yeast mitochondria. They found that mitochondrial outer and inner membrane fusion events were separable and mechanistically distinct, but both required GTP hydrolysis. Homotypic trans interactions of the ancient outer transmembrane GTPase, Fzo1 (see MFN1; 608506), were required to promote the fusion of mitochondrial outer membranes, whereas electrical potential was also required for fusion of inner membranes. Meeusen et al. (2004) found that outer membrane fusion required GTP and trans Fzo interactions on opposing mitochondria, suggesting that GTP promotes outer membrane fusion by means of Fzo1. The only known fusion protein associated with the inner membrane is the dynamin-related GTPase protein (DRP) Mgm1, of which OPA1 is the human ortholog. </p><p>Cipolat et al. (2004) determined that both the GTPase domain and the C-terminal coiled-coil domain of mouse Opa1 were required to promote the formation of branched network of elongated mitochondria in mouse embryonic fibroblasts. Stable reduction of Opa1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. The level of Opa1 did not affect mitochondrial docking, but it correlated with the extent of mitochondrial fusion. Using RNA interference against mouse Opa1 in Mfn1-null mouse embryonic fibroblasts, Cipolat et al. (2004) demonstrated an interdependence between Opa1 and Mfn1 in promoting mitochondrial elongation. </p><p>Using mouse embryonic fibroblasts, Frezza et al. (2006) showed that Opa1 regulated apoptosis by controlling cristae remodeling and cytochrome c redistribution. This function correlated with Opa1 oligomerization and was dependent on cleavage of Opa1 by Parl (607858). Frezza et al. (2006) concluded that oligomerization of OPA1 regulates apoptosis by maintaining the tightness of cristae junctions. </p><p>Olichon et al. (2007) found that silencing of exon 4-containing OPA1 variants in HeLa cells led to the disappearance of the 4 most abundant OPA1 isoforms, whereas silencing of variants containing exon 4b or 5b had little effect. Overexpression and knockdown studies showed that OPA1 isoforms containing domain 4, but not those containing domain 4b or 5b, were involved in maintenance of the mitochondrial membrane potential and fusion of the mitochondrial network. Conversely, knockdown of variants containing exon 4b or 5b led to apoptosis in the absence of mitochondrial morphologic changes or dissipation of the membrane potential. </p><p>Using conditional gene targeting, Merkwirth et al. (2008) restricted expression of mouse prohibitin-2 (PHB2; 610704) to mitochondria and identified processing of Opa1 as the central cellular process controlled by prohibitins. Deletion of Phb2 led to selective loss of long isoforms of Opa1, resulting in aberrant cristae morphogenesis, impaired cellular proliferation, and resistance to apoptosis. Expression of a long Opa1 isoform in Phb2-deficient cells suppressed these defects, identifying impaired Opa1 processing as the primary cellular defect in the absence of prohibitins. Merkwirth et al. (2008) concluded that prohibitins are essential for Opa1-dependent formation of mitochondrial cristae. </p><p>By immunostaining, Amati-Bonneau et al. (2005) found that the OPA1 protein was ubiquitously distributed in sensory and neural cochlear cells of the guinea pig. </p><p>Mitochondrial nucleoids are autonomous replication units that contain 6 to 10 copies of mitochondrial DNA (mtDNA) and associated proteins. Elachouri et al. (2011) found that a 10-kD peptide generated by proteolytic processing of an OPA1 isoform containing domain 4b localized to mitochondrial nucleoids. This peptide, designated NT-OPA1-exon4b, was generated by proteolytic removal of the mitochondrial localization signal followed by YME1L (607472)-mediated cleavage within the exon 5-encoded domain, which released the C-terminal GTPase domain and GED. Fractionation and biochemical analysis showed that NT-OPA1-exon4b bound to the inner mitochondrial membrane, and chromatin immunoprecipitation studies showed that it also bound to nucleoid DNA. Knockdown of exon 4b-containing OPA1 variants inhibited mtDNA replication and altered the size and distribution of nucleoids. Elachouri et al. (2011) concluded that NT-OPA1-exon4b influences replication of mtDNA. </p><p>Ban et al. (2010) showed that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids, such as cardiolipin. Lipid association triggered assembly of OPA1 into higher order oligomers. In addition, OPA1 could promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies were observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 was suppressed by GTP-gamma-S. OPA1 disease alleles associated with dominant optic atrophy displayed selective defects in several activities, including cardiolipin association, GTP hydrolysis, and membrane tubulation. Ban et al. (2010) concluded that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis, and lead to membrane deformation into tubules. </p><p>Kasahara et al. (2013) found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mfn1 (608506) and Mfn2 (608507) in the embryonic mouse heart, or gene trapping of Mfn2 or Opa1 in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (190180)/Bmp (see 112264), serum response factor (SRF; 600589), Gata4 (600576), and myocyte enhancer factor-2, linked to increased calcium-dependent calcineurin (see 114105) activity and Notch1 (190198) signaling that impaired embryonic stem cell differentiation. Kasahara et al. (2013) concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling. </p><p>Head et al. (2009) found that human OMA1 (617081) is the protease that cleaves long isoforms of OPA1 in response to mitochondrial stress. </p><p>An et al. (2013) found that knockdown of HIGD1A (618623) in HEK293T and HeLa cells resulted in mitochondria fragmentation, disorganization of mitochondrial cristae, and inhibition of proliferation. HIGD1A knockdown led to cleavage of OPA1, resulting in loss of the OPA1 long isoform and accumulation of small soluble forms. Overexpression of HIGD1A partially inhibited OPA1 cleavage, conserved mitochondrial morphology, and prolonged cell survival. Immunoprecipitation and mutation analyses demonstrated that the N-terminal tail of HIGD1A bound OPA1. Overexpression of a noncleavable long OPA1 isoform alleviated growth retardation in HIGD1A-knockdown HEK293T cells. </p><p>In nonstressed cells, the mitochondrial intermembrane space is locked inside cristae by protein complexes containing the long isoform of OPA1 (L-OPA1). Using U2OS human osteosarcoma cells engineered to inducibly express BIM (BCL2L11; 603827), which is the upstream activator of proapoptotic BAX-BAK1, Jiang et al. (2014) found that OMA1 was required for L-OPA1 cleavage and BIM-dependent apoptosis. Short hairpin-mediated knockdown of OMA1, or CRISPR-mediated deletion of OMA1, abrogated BIM-dependent cleavage of L-OPA1, disassembly of OPA1-containing complexes, cytochrome c and SMAC (DIABLO; 605219) release from mitochondria, and mitochondrial fragmentation. Further knockdown and mutation studies supported the critical role of OMA1 downstream of BIM and BAX-BAK1 in L-OPA1 cleavage and release from cristae protein complexes, and loss of mitochondrial membrane permeability. </p><p>Both YME1L1 (607472) and OMA1 convert long forms of OPA1 to short forms of OPA1. Wai et al. (2015) found that targeted deletion of Yme1l in mouse cardiomyocytes induced proteolytic cleavage of Opa1 by Oma1 and drove fragmentation of mitochondria. Ymel1 mutant mice suffered from dilated cardiomyopathy, heart failure, and early death, with a metabolic switch from fatty oxidation toward glucose utilization. Cardiac function, longevity, and metabolic profiles in Yme1l mice were reversed by supplemental deletion of Yme1l in skeletal muscle, an insulin-signaling tissue, although fragmented mitochondria were detected in Yme1l knockout cardiomyocytes. Feeding a high-fat diet to cardiomyocyte knockout Yme1l mutant mice also protected them from cardiac and metabolic defects, without restoring mitochondrial morphology. Knockout of both Oma1 and Yme1l in cardiomyocytes prevented conversion of L-Opa1 to S-Opa1 forms and restored normal mitochondrial architecture, in addition to protecting Yme1l mutant mice from cardiomyopathy and early death. Wai et al. (2015) concluded that mitochondrial fusion mediated by L-OPA1 preserves cardiac function, whereas its stress-induced processing by OMA1 and mitochondrial fragmentation triggers dilated cardiomyopathy and heart failure, and that deleterious effects of mitochondrial fragmentation in cardiomyocytes can be circumvented by metabolic intervention. </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>Heterozygous OPA1 Mutations</em></strong></p><p>
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In 6 unrelated families with dominant optic atrophy, Delettre et al. (2000) identified 4 different heterozygous mutations in the OPA1 gene (605290.0001-605290.0004). One of the mutations was found in 3 families who were apparently unrelated but who all originated from the northern French provinces and Belgium. Alexander et al. (2000) identified mutations in the OPA1 gene in 7 independent families. </p><p>Pesch et al. (2001) identified heterozygous mutations in the OPA1 gene in 25 of 78 independent autosomal dominant optic atrophy families screened. Most missense mutations clustered within the putative GTPase domain, and there was a preponderance of mutations that resulted in premature translation termination. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation. Their observations supported the notion that haploinsufficiency may represent a major pathomechanism for dominant optic atrophy. In addition, Pesch et al. (2001) identified a patient who was a compound heterozygote for 2 OPA1 missense mutations. The patient was much more severely affected than her simple heterozygotic parents and sibs, implying that these OPA1 alleles can behave semidominantly or recessively rather than purely dominantly. </p><p>Toomes et al. (2001) found mutations in OPA1 in 20 of 35 dominant optic atrophy patients screened. The predominance of null mutations further suggests that the mechanism underlying optic atrophy is haploinsufficiency. To investigate whether LHON could be caused by mutations in OPA1, the authors also screened a panel of 28 LHON patients who tested negatively for the 3 major LHON mutations. No mutations were identified in any LHON patients, indicating that dominant optic atrophy and LHON are genetically distinct. </p><p>Delettre et al. (2001) screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found 15 different mutations, 8 of which were novel, in 17 (89%) patients. Most of the mutations were truncating (65%) and located in exons 8 to 28, but a number of them were amino acid changed located predominantly in the GTPase domain in exons 8 to 15. Delettre et al. (2001) hypothesized that at least 2 modifications of OPA1 may lead to dominant optic atrophy: alteration in GTPase activity and loss of the last 7 C-terminal amino acids that putatively interact with other proteins. </p><p>Shimizu et al. (2003), Li et al. (2005), and Amati-Bonneau et al. (2005) identified the same heterozygous mutation in the OPA1 gene (R445H; 605290.0011) in several unrelated patients with optic atrophy, deafness, and neuromuscular complications (125250), suggesting that this mutation is specifically associated with the phenotype. </p><p>In patients with dominant optic atrophy, Schimpf et al. (2006) identified and characterized 4 intronic and 3 exonic OPA1 gene mutations that caused a variety of splicing defects and transcript processing defects, including activation of cryptic splice sites. </p><p>Schimpf et al. (2008) analyzed OPA1 transcripts from 37 different OPA1 mutations, including 22 novel mutations, from 42 OPA1 patients or families. These included 11 missense, 3 nonsense, and 15 splice site mutations, and 7 deletions and/or insertions. All missense mutations were located in the GTPase domain: 8 resulted in an amino acid exchange, and 3 were in the last or penultimate nucleotide of an exon, resulting in a leaky splice defect. Eleven splice site mutations resulted in complete skipping of an adjacent exon, whereas 4 resulted in activation of a cryptic splice site. Using pyrosequencing technology, Schimpf et al. (2008) demonstrated that nonsense or frameshift mutations were associated with a 20 to 50% reduced level of mutant mRNA transcripts in corresponding patient samples, although these levels varied between family members with the same mutation and between blood and lymphoblastoid cells from the same individual. RNA transcripts from lymphoblastoid cells were less stable compared to blood samples. These findings suggested that nonsense-mediated decay occurs to a different degree depending on specific mutation type or location, as well as cell or tissue type. Schimpf et al. (2008) concluded that haploinsufficiency of OPA1 is the pathomechanism in this disorder. </p><p>Using multiplex ligation probe amplification (MLPA), Fuhrmann et al. (2009) identified heterozygous deletions of 1 or more exons in the OPA1 gene in 5 of 42 OPA1 probands who did not have point mutations by previous screening techniques. Three additional probands had a heterozygous in-frame duplication of exons 7 to 9. Overall, the results were consistent with haploinsufficiency as a disease mechanism rather than gain of function. Fuhrmann et al. (2009) estimated that OPA1 genomic rearrangements have a prevalence of 12.9% in patients with autosomal dominant optic atrophy. </p><p>Yu-Wai-Man et al. (2010) investigated the mtDNA changes induced by OPA1 mutations in skeletal muscle biopsies from 15 patients with either isolated dominant optic atrophy (DOA; 165500) or the multisystem neurologic disorder DOA+ (125250). There was a 2- to 4-fold increase in mtDNA copy number at the single-fiber level, and patients with DOA+ features had significantly greater mtDNA proliferation in their cytochrome c oxidase (COX; see 516030)-negative skeletal muscle fibers compared to patients with isolated optic neuropathy. Low levels of wildtype mtDNA molecules were present in COX-deficient muscle fibers from both isolated DOA and DOA+ patients, implicating haploinsufficiency as the mechanism responsible for the biochemical defect. The authors suggested that their findings were consistent with a 'maintenance of wildtype' hypothesis, with secondary mtDNA deletions induced by OPA1 mutations triggering a compensatory mitochondrial proliferative response to maintain an optimal level of wildtype mtDNA genomes. However, when deletion levels reach a critical level, further mitochondrial proliferation may lead to replication of the mutant species at the expense of wildtype mtDNA, resulting in the loss of respiratory chain COX activity. </p><p>In a 27-year-old Italian woman and her 57-year-old mother with DOA+, Napolitano et al. (2020) identified heterozygosity for a missense mutation in the OPA1 gene (R445H; 605290.0011). The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (606441) was increased in the muscle tissue of both patients, although more so in the daughter. Napolitano et al. (2020) hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation. </p><p><strong><em>Behr Syndrome</em></strong></p><p>
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|
In 2 sibs with Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: I382M (605290.0018) and a 4-bp deletion (605290.0003). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) concluded that the missense mutation may be a mild mutation and shows strong additive effects when combined with a second mutation. The more severe phenotype in the children was consistent with autosomal recessive or semidominant inheritance of the disorder. </p><p>In 3 unrelated patients with Behr syndrome, Bonneau et al. (2014) identified compound heterozygosity for the I382M substitution in the OPA1 gene on 1 allele and different mutations on the other (see, e.g., 605290.0020). A fourth patient was compound heterozygous for 2 different mutations (605290.0003 and 605290.0021). There was no evidence that any of the parents who were heterozygous carriers of the I382M substitution had optic atrophy, but DNA was not available from all asymptomatic parents. Functional studies of the variants were not performed. </p><p><strong><em>Mitochondrial DNA Depletion Syndrome 14</em></strong></p><p>
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In 2 sisters, born of consanguineous Arab parents, with mitochondrial DNA depletion syndrome-14 (MTDPS14; 616896) resulting in fatal infantile cardioencephalomyopathy, Spiegel et al. (2016) identified a homozygous missense mutation in the OPA1 gene (L534R; 605290.0023). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities. </p><p><strong><em>Normal Tension Glaucoma</em></strong></p><p>
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Normal tension glaucoma (NTG; 606657) is an important subtype of primary open angle glaucoma, in which the intraocular pressure (IOP) is consistently within the statistically normal population range. Aung et al. (2002) screened 83 well-characterized NTG patients for mutations in the OPA1 gene by heteroduplex analysis and bidirectional sequencing. In this and a second cohort of 80 NTG patients, they found that a single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8, IVS8+4C/T, was strongly associated with the occurrence of NTG. A second SNP, IVS8+32T/C, appeared to be associated with disease in the first cohort, but this finding could not be replicated in a second cohort. In the combined cohort, the compound at-risk genotype IVS8+4C/T,+32T/C (605290.0010) was strongly associated with the occurrence of NTG (P = 0.00001 after correcting for testing of 4 genotypes). These results indicated that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Among 104 patients from 45 families with 33 different OPA1 mutations, Yu-Wai-Man et al. (2010) found that multisystem neurologic disease involving optic atrophy, deafness, and neuromuscular complications (125250) was associated with all types of mutations; however, there was an increased risk with missense mutations (odds ratio (OR) of 3.06, p = 0.0027) and with mutations located within the GTPase region (OR of 2.29, p = 0.0271). Skeletal muscle biopsies from those with extraocular neurologic features showed higher levels of cytochrome c oxidase-deficient fibers and mitochondrial DNA deletions compared to those with pure optic neuropathy, suggesting a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. </p><p>To analyze the influence of OPA1 gene mutations on optic nerve head morphology in patients with dominant optic atrophy, Barboni et al. (2010) studied the optic nerve head of 28 OPA1 mutation-positive patients from 11 pedigrees and 56 age-matched controls by optical coherence tomography (OCT). Patients showed a significantly smaller optic disc area (P less than 0.0001), and vertical (P = 0.018), and horizontal (P less than 0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal optic nerve head area with 2 mutations, whereas a missense mutation linked to a 'dominant optic atrophy plus' phenotype (605290.0017) had the smallest ONH measurements. Barboni et al. (2010) concluded that their observations suggested a theretofore unrecognized role for OPA1 in eye development, and in particular in modeling optic nerve head size and conformation. </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>Davies et al. (2007) generated mutant mice carrying an ethylnitrosourea (ENU)-induced Q285X mutation in the Opa1 gene, resulting in a truncated protein. Western analysis showed that the mutation resulted in approximately 50% reduction in Opa1 protein in retina and all tissues. The homozygous mutation was embryonic lethal by 13.5 days postcoitum. Fibroblasts from adult heterozygotes showed an increase in mitochondrial fission and fragmentation. In addition, electron microscopy revealed the slow onset of optic nerve degeneration; reduced visual function in heterozygotes was demonstrated by optokinetic drum testing and the circadian running wheel. Davies et al. (2007) concluded that the OPA1 GTPase contains crucial information required for the survival of retinal ganglion cells and that OPA1 is essential for early embryonic survival. </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>23 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 OPTIC ATROPHY 1</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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OPA1, GLY300GLU
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<br />
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SNP: rs28939082,
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ClinVar: RCV000005385, RCV005089178
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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 one family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found an 899G-A transition in exon 9 of the OPA1 gene that changed glycine to glutamic acid at codon 300. </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 OPTIC ATROPHY 1</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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OPA1, IVS9AS, G-A, -1
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<br />
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SNP: rs879255510,
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ClinVar: RCV000005386, RCV000518060
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found a G-to-A transition in the last nucleotide of intron 9 of the OPA1 gene that abolished the acceptor splice site. This mutation results in either skipping of exon 10 with no frameshift in the following exon 11, or a frameshift with a premature stop at the first codon of exon 10 (329) if the newly ectopic acceptor splice site 1 bp downstream of the original is functional. </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 OPTIC ATROPHY 1</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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BEHR SYNDROME, INCLUDED
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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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OPA1, 4-BP DEL, 2708TTAG
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<br />
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SNP: rs80356530,
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ClinVar: RCV000005387, RCV000081763, RCV000210745, RCV000508703, RCV001073751, RCV001542739, RCV002490322, RCV003319160, RCV004532291, RCV004584316, RCV004798716, RCV004814831
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the OPA1 gene, 2708delTTAG, that caused 2 amino acid substitutions (val903 to gly, arg904 to asp) and a premature stop at codon 905. This mutation was present in an asymptomatic carrier in one family but was fully penetrant in the other 2 families. This penetrance was expected since minimally affected patients and asymptomatic carriers (with no detectable optic atrophy on fundus examination) had been described. The 3 families were apparently unrelated, but all originated from the northern French provinces and Belgium. Founder effect had been demonstrated by haplotype studies in the British Isles (Votruba et al., 1998; Johnston et al., 1999). </p><p>Toomes et al. (2001) haplotyped 8 unrelated individuals with the 2708delTTAG mutation and concluded that this may be a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. A recalculation of the penetrance of this disorder within 2 of 8 families indicated figures as low as 43% and 62% associated with the 2708delTTAG mutation. </p><p>In 2 sibs with clinical features of Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: 2708delTTAG and I382M (605290.0018). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) considered the more severe phenotype in the children to be consistent with semidominant inheritance. </p><p>In an 11-year-old girl with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: a 4-bp deletion (c.2708_2711) in exon 27, resulting in a frameshift and premature termination (Val903GlyfsTer), and a c.1204G-A transition in exon 12, resulting in a val402-to-met (V402M; 605290.0021) substitution. </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 OPTIC ATROPHY 1</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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OPA1, 4-BP DEL, 2823AGTT
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<br />
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SNP: rs879255560,
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ClinVar: RCV000005388, RCV000355298, RCV004814832
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found a 4-bp deletion in exon 28 of the OPA1 gene (2823delAGTT) that caused a delayed stop, downstream of the original one, resulting in the replacement of the last 19 amino acids of the protein with 24 novel amino acids at the carboxy terminus. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 OPTIC ATROPHY 1</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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OPA1, ARG290GLN
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<br />
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SNP: rs121908375,
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ClinVar: RCV000005389, RCV000790668, RCV001336297, RCV004814833
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a family from Cuba, Alexander et al. (2000) demonstrated that members with autosomal dominant optic atrophy (165500) had a G-to-A transition of nucleotide 869 in exon 8 of the OPA1 gene, predicting an arg290-to-gln amino acid change. </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 OPTIC ATROPHY 1</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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OPA1, ARG366TER
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<br />
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SNP: rs104893752, rs104893753,
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ClinVar: RCV000005390, RCV000790742, RCV003225922, RCV004814834
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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 German family, Alexander et al. (2000) found that individuals with autosomal dominant optic atrophy (165500) had a C-to-T transition of nucleotide 1096 in exon 11 of the OPA1 gene, predicted to cause an arg366-to-ter change in the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0007 OPTIC ATROPHY 1</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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OPA1, 3-BP DEL, 1296CAT
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<br />
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SNP: rs879255511,
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ClinVar: RCV000005391
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In affected members of a U.K. family with autosomal dominant optic atrophy (165500), Alexander et al. (2000) found a 3-bp deletion, del1296CAT, in exon 13 of the OPA1 gene resulting in deletion of the amino acid isoleucine-432. </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>.0008 OPTIC ATROPHY 1</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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OPA1, 1-BP DEL, 1354G
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<br />
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SNP: rs879255512,
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ClinVar: RCV000005392
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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 second German family with autosomal dominant optic atrophy (165500), Alexander et al. (2000) found that affected members had a 1-bp deletion in the OPA1 gene, 1354delG, causing a frameshift followed by 14 novel amino acids before termination. </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>.0009 OPTIC ATROPHY 1</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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OPA1, 1-BP DEL, 2826T
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<br />
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SNP: rs80356531,
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ClinVar: RCV000005393
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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>The prevalence of Kjer type optic atrophy (165500) is reported to be highest in Denmark of any geographic area, suggesting a founder effect. In a sample of 33 apparently unrelated Danish families, Thiselton et al. (2001) screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. In 14 pedigrees, a novel identical mutation in exon 28, 2826delT, was associated with dominant optic atrophy and led to a frameshift and an abnormal C terminus of the OPA1 protein. Haplotype analysis revealed a common haplotype shared by all 14 patients; this haplotype was markedly overrepresented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with dominant optic atrophy over approximately 600 kb encompassing the disease mutation. The authors concluded that a founder mutation is responsible for approximately 42% of the families studied and suggested that presymptomatic screening for the 2826delT mutation may facilitate diagnosis and genetic counseling. The disorder is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density. </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>.0010 GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO</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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OPA1, IVS8, C-T, +4 AND IVS8, T-C, +32
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<br />
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SNP: rs10451941, rs166850,
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gnomAD: rs10451941, rs166850,
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ClinVar: RCV000005394, RCV000081772, RCV001711248
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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>Aung et al. (2002) found a strong association of normal tension glaucoma (NTG; 606657) with the T allele at the IVS8+4C/T SNP in combination with the C allele at the IVS8+32T/C SNP of the OPA1 gene in Caucasians. In a second publication, Aung et al. (2002) found no significant association of this double polymorphism of intron 8 of the OPA1 gene in high-tension primary open angle glaucoma, suggesting a fundamental difference between the 2 forms. </p><p>Mabuchi et al. (2007) found a significant association of NTG with the IVS8+32C-T SNP, but not with the IVS8+4C-T SNP, in Japanese. </p><p>In 137 patients with primary open angle glaucoma (POAG), including 67 with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from the northeast of England, Yu-Wai-Man et al. (2010) found significant association between the T allele at IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004) but not HTG. Logistic regression analysis confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (odds ratio, 29.75; p = 0.001). Yu-Wai-Man et al. (2010) concluded that the CT/TT compound genotype in intron 8 of the OPA1 gene is a strong genetic risk determinant for NTG but not HTG. </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>.0011 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</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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OPA1, ARG445HIS
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<br />
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SNP: rs80356529,
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ClinVar: RCV000005396, RCV000081749, RCV000508953, RCV003137493, RCV003492285, RCV004585987, RCV004814835
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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 Japanese patient with optic atrophy and moderate sensorineural deafness (125250), Shimizu et al. (2003) identified a heterozygous G-to-A transition in the second nucleotide at codon 445 in the OPA1 gene, resulting in an arg445-to-his (R445H) substitution in the GTPase domain. </p><p>Payne et al. (2004) found this mutation in a large Utah family and an unrelated Belgian family, previously described by Treft et al. (1984) and Meire et al. (1985), respectively. Both families had optic atrophy, deafness, and ophthalmoplegia. The authors hypothesized that, although OPA1 is a nuclear gene, the localization of its gene product to mitochondria suggests that mitochondrial dysfunction might be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia. </p><p>In a third family with optic atrophy and hearing loss, unrelated to the Utah or Belgian families, Li et al. (2005) identified the R445H mutation. Li et al. (2005) noted that affected members of this family did not have extraocular motility abnormalities or ptosis, thus illustrating the intra- and interfamilial phenotype variability associated with this mutation. </p><p>Amati-Bonneau et al. (2005) identified the R445H mutation in 5 unrelated patients from 4 families with optic atrophy and deafness, thus confirming that this mutation is specifically associated with hearing loss. One of the patients had been previously reported by Amati-Bonneau et al. (2003). In the Spanish mother and daughter previously reported by Amati-Bonneau et al. (2005), Amati-Bonneau et al. (2008) noted that the mother had additional features including myopathy, neuropathy, and progressive external ophthalmoplegia. </p><p>Stewart et al. (2008) identified the R445H mutation in 2 probands with optic atrophy and myopathy associated with mitochondrial DNA deletions. One proband also had deafness. The other proband did not have hearing loss, but 3 affected family members had hearing loss. </p><p>In a 27-year-old Italian woman and her 57-year-old mother with DOA+, Napolitano et al. (2020) identified heterozygosity for the mutation in the OPA1 gene (R445H; 605290.0011). The mutation was identified by Sanger sequencing of the OPA1 gene. The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (606441) was increased in the muscle tissue of both patients, although more so in the daughter. Napolitano et al. (2020) hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 OPTIC ATROPHY 1</strong>
|
|
</span>
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|
</h4>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
OPA1, 2-BP DEL, 2848GA
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|
<br />
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|
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SNP: rs879255513,
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|
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ClinVar: RCV000005397, RCV000023413
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Chinese family in which 9 members had autosomal dominant optic atrophy (165500), accompanied in some by high frequency hearing loss (125250) and/or myopia, Chen et al. (2007) identified a 2-bp deletion in exon 28 of the OPA1 gene (2848_2849delGA), which resulted in a premature stop at codon 953 and a loss of the last 11 amino acids of the protein, in all affected members. The mutation was absent in a family member with myopia alone as well as in all unaffected family members and 100 normal controls. </p>
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, TYR582CYS
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|
<br />
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|
|
SNP: rs121908376,
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|
|
|
ClinVar: RCV000005395
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with progressive external ophthalmoplegia, visual loss, hearing loss, and mild myopathy and ataxia (125250), Ferraris et al. (2008) identified a heterozygous 1741A-G transition in the OPA1 gene, resulting in a tyr582-to-cys (Y582C) substitution. The patient was also found to carry a gly416-to-ala (G416A) variant in the POLG2 gene (604983), but in vitro functional studies showed no functional deficits of the POLG2 variant. Ferraris et al. (2008) concluded that the OPA1 mutation was responsible for the phenotype. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, ILE432VAL
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs387906899,
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|
|
ClinVar: RCV000023414, RCV000508763, RCV004786281
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a brother and sister with optic atrophy, progressive external ophthalmoplegia, myopathy, ataxia, but no hearing loss (125250), Stewart et al. (2008) identified heterozygosity for a 1294A-G transition in the OPA1 gene, resulting in an ile432-to-val (I432V) substitution in the GTPase domain. The mutation was not detected in 344 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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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, SER545ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398124298,
|
|
|
|
|
|
|
|
ClinVar: RCV000023415, RCV000508898, RCV001659726, RCV002464072, RCV004814921
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 affected members of a 3-generation family with optic atrophy, ataxia, and progressive external ophthalmoplegia (125250), Hudson et al. (2008) identified heterozygosity for a 1635C-G transversion in exon 17 of the OPA1 gene, resulting in a ser545-to-arg (S545R) substitution in the GTPase domain. Three patients had deafness with onset in the third or fourth decade, and 3 patients had neuropathy and myopathy. </p><p>In 3 affected members of an Austrian family with optic atrophy, deafness, progressive external ophthalmoplegia, ataxia, and neuropathy (125250), Yu-Wai-Man et al. (2010) identified a heterozygous S545R mutation, which they noted was in the dynamin domain of the protein. Two patients in their thirties had deafness, whereas an older family member in her sixties did not have deafness. The authors also identified the S545R mutation in a 30-year-old French man with optic atrophy, deafness, ataxia, myopathy, and neuropathy. </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>.0016 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, GLY439VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906900,
|
|
|
|
|
|
|
|
ClinVar: RCV000023416, RCV001857360
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian man with optic atrophy, deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (125250), Amati-Bonneau et al. (2008) identified a heterozygous 1316G-T transversion in exon 14 of the OPA1 gene, resulting in a gly439-to-val (G439V) substitution in the GTPase domain. His 7-year-old daughter also carried the G439V mutation and had optic atrophy and deafness. The mutation was not identified in 460 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, VAL910ASP
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906901,
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|
|
|
|
|
|
|
ClinVar: RCV000023417
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|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian man with optic atrophy, deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (125250), Amati-Bonneau et al. (2008) identified a 2729T-A transversion in exon 27 of the OPA1 gene, resulting in a val910-to-asp substitution (V910D). At least 6 other members of the family were affected. This mutation resides outside the GTPase domain, at the interface of the 2 effector domains performing the conformational change, and was associated with a milder phenotype than that of other families included in the study. </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>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 OPTIC ATROPHY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BEHR SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, ILE382MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs143319805,
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|
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|
|
|
gnomAD: rs143319805,
|
|
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|
|
|
ClinVar: RCV000043607, RCV000081747, RCV000210748, RCV000677258, RCV001249638, RCV001267306, RCV003993775, RCV004537182, RCV004814984
|
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|
|
</span>
|
|
</div>
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autosomal dominant optic atrophy (165500), Schimpf et al. (2008) identified a heterozygous 1146A-G transition in the OPA1 gene, resulting in an ile382-to-met (I382M) substitution at a conserved residue in the GTPase domain. The mutation was not found in 100 controls. No clinical information was provided. </p><p>In 2 sibs with Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: I382M and a 4-bp deletion (605290.0003). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) concluded that the missense mutation may be a mild mutation and shows strong additive effects when combined with a second mutation. The more severe phenotype in the children was consistent with autosomal recessive or semidominant inheritance of the disorder. </p><p>In 3 unrelated patients with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: each patient carried the I382M substitution in exon 12 on 1 allele and a different mutation on the other allele (see, e.g., 605290.0020). There was no evidence that any of the parents who were heterozygous carriers of the I382M substitution had optic atrophy, but DNA was not available from all asymptomatic parents. Functional studies of the variants were not performed. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
OPA1, CYS551TYR
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs879255592,
|
|
|
|
|
|
|
|
ClinVar: RCV000210742
|
|
|
|
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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 adult brothers with optic atrophy without deafness, but with ataxia, neuropathy, and spasticity (125250), Marelli et al. (2011) identified a heterozygous c.1652G-A transition in exon 17 of the OPA1 gene, resulting in a cys551-to-tyr (C551Y) substitution at a highly conserved residue in the dynamin domain. Their asymptomatic mother did not carry the mutation; DNA from the apparently unaffected father was not available. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0020 BEHR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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OPA1, ARG824TER
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<br />
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SNP: rs879255593,
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ClinVar: RCV000210747, RCV001073476, RCV003133183
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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 14-year-old boy with Behr syndrome (BEHRS; 210000), Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: a c.2470C-T transition in exon 24, resulting in an arg824-to-ter (R824X) substitution, and a c.1146A-G transition in exon 12, resulting in an ile382-to-met (I382M; 605290.0018) substitution. The mother, who had mild optic atrophy, carried the R824X mutation; DNA from the asymptomatic father was not available. The patient had mildly delayed psychomotor development, optic atrophy, ataxia, dysmetria, and axonal sensory neuropathy; he required assistance for ambulation after age 8. Brain imaging showed mild cerebellar atrophy and periventricular white matter abnormalities. </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>.0021 BEHR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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OPA1, VAL402MET
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<br />
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SNP: rs879255594,
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ClinVar: RCV000210739, RCV003556273
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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.1204G-A transition in exon 12 of the OPA1 gene resulting in a val402-to-met (V402M) substitution that was found in compound heterozygous state in a patient with Behr syndrome (BEHRS; 210000) by Bonneau et al. (2014), see 605290.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0022 BEHR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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OPA1, IVS17DS, G-T, +1
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<br />
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SNP: rs879255595,
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ClinVar: RCV000210744
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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 20-year-old Italian man with Behr syndrome (BERHS; 210000), Carelli et al. (2015) identified compound heterozygous mutations in the OPA1 gene: a G-to-T transversion in intron 17 (c.1705+1G-T), resulting in a splice site mutation, premature termination and functional haploinsufficiency, and I382M (605190.0018). The patient's mother and several maternal relatives with isolated optic atrophy were heterozygous for the splice site mutation, but there was also evidence of incomplete penetrance for this mutation. The father, who was heterozygous for the I382M mutation, was clinically unaffected, suggesting that it may be a hypomorphic mutation. </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>.0023 MITOCHONDRIAL DNA DEPLETION SYNDROME 14 (ENCEPHALOCARDIOMYOPATHIC TYPE) (1 family)</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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OPA1, LEU534ARG
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<br />
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SNP: rs869312995,
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ClinVar: RCV000210746
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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 sisters, born of consanguineous Arab parents, with mitochondrial DNA depletion syndrome-14 (MTDPS14; 616896), Spiegel et al. (2016) identified a homozygous c.1601T-G transversion (c.1601T-G, NM_015560.2) in the OPA1 gene, resulting in a leu534-to-arg (L534R) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the ExAC database or in 120 ethnically matched controls. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. The patients showed hypotonia, peripheral hypertonia, profound neurodevelopmental delay, optic atrophy, and normal lactate. Both developed progressive hypertrophic cardiomyopathy and died in infancy. Skeletal muscle biopsies showed a global decrease in all mitochondrial respiratory chain activities, with complexes I and IV being the most affected, as well as significant mtDNA depletion, with a 78% decrease compared to controls. Electron microscopy of 1 patient showed large mitochondria with incomplete fusion of the inner mitochondrial membrane. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities. </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>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">
|
|
Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., Wissinger, B.
|
|
<strong>OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.</strong>
|
|
Nature Genet. 26: 211-215, 2000.
|
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|
|
[PubMed: 11017080]
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[Full Text: https://doi.org/10.1038/79944]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P.
|
|
<strong>OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.</strong>
|
|
Ann. Neurol. 58: 958-963, 2005.
|
|
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|
|
[PubMed: 16240368]
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[Full Text: https://doi.org/10.1002/ana.20681]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Amati-Bonneau, P., Odent, S., Derrien, C., Pasquier, L., Malthiery, Y., Reynier, P., Bonneau, D.
|
|
<strong>The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene.</strong>
|
|
Am. J. Ophthal. 136: 1170-1171, 2003.
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|
|
[PubMed: 14644237]
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[Full Text: https://doi.org/10.1016/s0002-9394(03)00665-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others.
|
|
<strong>OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.</strong>
|
|
Brain 131: 338-351, 2008.
|
|
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|
|
[PubMed: 18158317]
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|
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[Full Text: https://doi.org/10.1093/brain/awm298]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
An, H.-J., Cho, G., Lee, J.-O., Paik, S.-G., Kim, Y. S., Lee, H.
|
|
<strong>Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria.</strong>
|
|
Proc. Nat. Acad. Sci. 110: 13014-12019, 2013.
|
|
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|
|
[PubMed: 23878241]
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[Full Text: https://doi.org/10.1073/pnas.1307170110]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Brice, G., Child, A. H., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S.
|
|
<strong>Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma.</strong>
|
|
Hum. Genet. 110: 513-514, 2002.
|
|
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|
|
[PubMed: 12073024]
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|
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[Full Text: https://doi.org/10.1007/s00439-002-0711-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S.
|
|
<strong>A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.</strong>
|
|
Hum. Genet. 110: 52-56, 2002.
|
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|
|
[PubMed: 11810296]
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[Full Text: https://doi.org/10.1007/s00439-001-0645-7]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ban, T., Heymann, J. A. W., Song, Z., Hinshaw, J. E., Chan, D. C.
|
|
<strong>OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.</strong>
|
|
Hum. Molec. Genet. 19: 2113-2122, 2010.
|
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|
|
[PubMed: 20185555]
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[Full Text: https://doi.org/10.1093/hmg/ddq088]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Barboni, P., Carbonelli, M., Savini, G., Foscarini. B., Parisi, V., Valentino, M. L., Carta, A., De Negri, A., Sadun, F., Zeviani, M., Sadun, A. A., Schimpf, S., Wissinger, B., Carelli, V.
|
|
<strong>OPA1 mutations associated with dominant optic atrophy influence optic nerve head size.</strong>
|
|
Ophthalmology 117: 1547-1553, 2010.
|
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|
|
[PubMed: 20417568]
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[Full Text: https://doi.org/10.1016/j.ophtha.2009.12.042]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bonneau, D., Colin, E., Oca, F., Ferre, M., Chevrollier, A., Gueguen, N., Desquiret-Dumas, V., N'Guyen, S., Barth, M., Zanlonghi, X., Rio, M., Desguerre, I., Barnerias, C., Momtchilova, M., Rodriguez, D., Slama, A., Lenaers, G., Procaccio, V., Amati-Bonneau, P., Reynier, P.
|
|
<strong>Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.</strong>
|
|
Brain 137: e301, 2014. Note: Electronic Article.
|
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|
|
|
[PubMed: 25012220]
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|
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[Full Text: https://doi.org/10.1093/brain/awu184]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Carelli, V., Sabatelli, M., Carrozzo, R., Rizza, T., Schimpf, S., Wissinger, B., Zanna, C., Rugolo, M., La Morgia, C., Caporali, L., Carbonelli, M., Barboni, P., Tonon, C., Lodi, R., Bertini, E.
|
|
<strong>'Behr syndrome' with OPA1 compound heterozygote mutations.</strong>
|
|
Brain 138: e321, 2015. Note: Electronic Article.
|
|
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|
|
[PubMed: 25146916]
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[Full Text: https://doi.org/10.1093/brain/awu234]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chen, S., Zhang, Y., Wang, Y., Li, W., Huang, S., Chu, X., Wang, L., Zhang, M., Liu, Z.
|
|
<strong>A novel OPA1 mutation responsible for autosomal dominant optic atrophy with high frequency hearing loss in a Chinese family.</strong>
|
|
Am. J. Ophthal. 143: 186-188, 2007.
|
|
|
|
|
|
[PubMed: 17188070]
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|
|
[Full Text: https://doi.org/10.1016/j.ajo.2006.06.049]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Cipolat, S., Martins de Brito, O., Dal Zilio, B., Scorrano, L.
|
|
<strong>OPA1 requires mitofusin 1 to promote mitochondrial fusion.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 15927-15932, 2004.
|
|
|
|
|
|
[PubMed: 15509649]
|
|
|
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|
|
[Full Text: https://doi.org/10.1073/pnas.0407043101]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Davies, V. J., Hollins, A. J., Piechota, M. J., Yip, W., Davies, J. R., White, K. E., Nicols, P. P., Boulton, M. E., Votruba, M.
|
|
<strong>Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function.</strong>
|
|
Hum. Molec. Genet. 16: 1307-1318, 2007.
|
|
|
|
|
|
[PubMed: 17428816]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddm079]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Delettre, C., Griffoin, J.-M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., Lenaers, G., Belenguer, P., Hamel, C. P.
|
|
<strong>Mutation spectrum and splicing variants in the OPA1 gene.</strong>
|
|
Hum. Genet. 109: 584-591, 2001.
|
|
|
|
|
|
[PubMed: 11810270]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-001-0633-y]
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C. P.
|
|
<strong>Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.</strong>
|
|
Nature Genet. 26: 207-210, 2000.
|
|
|
|
|
|
[PubMed: 11017079]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/79936]
|
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|
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Elachouri, G., Vidoni, S., Zanna, C., Pattyn, A., Boukhaddaoui, H., Gaget, K., Yu-Wai-Man, P., Gasparre, G., Sarzi, E., Delettre, C., Olichon, A., Loiseau, D., Reynier, P., Chinnery, P. F., Rotig, A., Carelli, V., Hamel, C. P., Rugolo, M., Lenaers, G.
|
|
<strong>OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution.</strong>
|
|
Genome Res. 21: 12-20, 2011.
|
|
|
|
|
|
[PubMed: 20974897]
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|
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[Full Text: https://doi.org/10.1101/gr.108696.110]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ferraris, S., Clark, S., Garelli, E., Davidzon, G., Moore, S. A., Kardon, R. H., Bienstock, R. J., Longley, M. J., Mancuso, M., Rios, P. G., Hirano, M., Copeland, W. C., DiMauro, S.
|
|
<strong>Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.</strong>
|
|
Arch. Neurol. 65: 125-131, 2008.
|
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|
|
[PubMed: 18195150]
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[Full Text: https://doi.org/10.1001/archneurol.2007.9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., Bartoli, D., Polishuck, R. S., Danial, N. N., De Strooper, B., Scorrano, L.
|
|
<strong>OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.</strong>
|
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[Full Text: https://doi.org/10.1126/science.aad0116]
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Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others.
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<strong>Multi-system neurological disease is common in patients with OPA1 mutations.</strong>
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Brain 133: 771-786, 2010.
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[PubMed: 20157015]
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[Full Text: https://doi.org/10.1093/brain/awq007]
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Yu-Wai-Man, P., Sitarz, K. S., Samuels, D. C., Griffiths, P. G., Reeve, A. K., Bindoff, L. A., Horvath, R., Chinnery, P. F.
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<strong>OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules.</strong>
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Hum. Molec. Genet. 19: 3043-3052, 2010.
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[PubMed: 20484224]
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[Full Text: https://doi.org/10.1093/hmg/ddq209]
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Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F.
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<strong>OPA1 increases the risk of normal but not high tension glaucoma.</strong>
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J. Med. Genet. 47: 120-125, 2010.
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[PubMed: 19581274]
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[Full Text: https://doi.org/10.1136/jmg.2009.067512]
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Contributors:
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Hilary J. Vernon - updated : 10/15/2021<br>Bao Lige - updated : 10/14/2019<br>Patricia A. Hartz - updated : 08/18/2016<br>Cassandra L. Kniffin - updated : 4/5/2016<br>Ada Hamosh - updated : 1/31/2014<br>George E. Tiller - updated : 8/27/2013<br>George E. Tiller - updated : 8/16/2013<br>Cassandra L. Kniffin - updated : 5/22/2013<br>Jane Kelly - updated : 2/17/2012<br>Cassandra L. Kniffin - updated : 5/19/2011<br>Matthew B. Gross - updated : 5/18/2011<br>Patricia A. Hartz - updated : 4/11/2011<br>Marla J. F. O'Neill - updated : 1/20/2011<br>Marla J. F. O'Neill - updated : 8/25/2010<br>Cassandra L. Kniffin - updated : 3/26/2009<br>Cassandra L. Kniffin - updated : 3/16/2009<br>Cassandra L. Kniffin - updated : 1/7/2009<br>Patricia A. Hartz - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 3/4/2008<br>Jane Kelly - updated : 3/30/2007<br>Jane Kelly - updated : 3/23/2007<br>Paul J. Converse - updated : 2/20/2007<br>Cassandra L. Kniffin - updated : 3/27/2006<br>Marla J. F. O'Neill - updated : 10/25/2005<br>Jane Kelly - updated : 6/23/2005<br>Patricia A. Hartz - updated : 4/27/2005<br>Ada Hamosh - updated : 12/29/2004<br>Patricia A. Hartz - updated : 4/28/2003<br>Jane Kelly - updated : 2/14/2003<br>Victor A. McKusick - updated : 6/7/2002<br>Victor A. McKusick - updated : 1/25/2002<br>Victor A. McKusick - updated : 1/2/2002<br>Victor A. McKusick - updated : 12/6/2001<br>George E. Tiller - updated : 11/14/2001
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Victor A. McKusick : 9/26/2000
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