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Entry
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- *606441 - HTRA SERINE PEPTIDASE 2; HTRA2
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</form>
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<p />
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606441</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>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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>
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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="#animalModel">Animal Model</a>
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</li>
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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/606441">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>
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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>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000115317;t=ENST00000258080" 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=27429" 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=606441" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000115317;t=ENST00000258080" 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_001321727,NM_001321728,NM_013247,NM_145074,NR_135769,NR_135770,NR_135771,NR_135772" 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_013247" 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=606441" 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=05919&isoform_id=05919_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/HTRA2" 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/5870865,7019477,7672669,7672671,7672673,10121320,12652695,17376879,21614538,119620023,119620024,119620025,119620026,119620027,155676349,158257386,308219116,1012282649,1012282651" 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/O43464" 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=27429" 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=ENSG00000115317;t=ENST00000258080" 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=HTRA2" 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=HTRA2" 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+27429" 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/HTRA2" 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:27429" 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/27429" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr2&hgg_gene=ENST00000258080.8&hgg_start=74529405&hgg_end=74533556&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:14348" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606441[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=606441[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://gnomad.broadinstitute.org/gene/ENSG00000115317" 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.gwascentral.org/search?q=HTRA2" 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=HTRA2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://reseq.biosciencedbc.jp/resequence/GeneDetail.do?targetId=2&geneId=EG27429" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HTRA2&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/PA33836" 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:14348" 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/FBgn0038233.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:1928676" 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/HTRA2#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:1928676" 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/27429/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=27429" 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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:27429" 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=HTRA2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</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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606441
|
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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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HTRA SERINE PEPTIDASE 2; HTRA2
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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>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HTRA, E. COLI, HOMOLOG OF, 2<br />
|
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PROTEASE, SERINE, 25; PRSS25<br />
|
|
OMI
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HTRA2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HTRA2</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/389?start=-3&limit=10&highlight=389">2p13.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:74529405-74533556&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">2:74,529,405-74,533,556</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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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 />
|
|
</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=610297,617248" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/389?start=-3&limit=10&highlight=389">
|
|
2p13.1
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
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<p>The HTRA2 gene encodes a serine protease that localizes to the mitochondrial intermembrane space. Following apoptotic stimuli, HTRA2 can expose an inhibitor of apoptosis protein (IAP) binding motif, thus mediating cell death, or can mediate cell death via its serine protease activity (<a href="#17" class="mim-tip-reference" title="Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R. <strong>A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.</strong> Molec. Cell 8: 613-621, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583623</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00341-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583623">Suzuki et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using presenilin-1 (<a href="/entry/104311">104311</a>) as bait in a yeast 2-hybrid screen of fetal brain cDNA, <a href="#4" class="mim-tip-reference" title="Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K. G., West, A., Savopoulos, J., Hassan, N. J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J. B., Dingwall, C., Livi, G. P., Creasy, C. L. <strong>Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response.</strong> Europ. J. Biochem. 267: 5699-5710, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10971580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10971580</a>] [<a href="https://doi.org/10.1046/j.1432-1327.2000.01589.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10971580">Gray et al. (2000)</a> isolated a cDNA encoding PRSS25, which they called HTRA2. By screening an adult brain cDNA library, they obtained 3 different splice variants of HTRA2. The predominant HTRA2 variant encodes a 458-amino acid protein. HTRA2 shows extensive homology to the E. coli HtrA genes, which are essential for bacterial survival at high temperatures. HTRA2 is also homologous to HTRA1 (PRSS11; <a href="/entry/602194">602194</a>), which is differentially expressed in human osteoarthritic cartilage and after SV40 transformation of human fibroblasts. The HTRA2 protein is 85% identical to its mouse homolog. Northern blot analysis detected a major 1.9-kb HTRA2 transcript in all tissues tested, with highest levels in heart and skeletal muscle and variable distribution in brain regions. In human cell lines, HTRA2 was present as 2 polypeptides of 38 and 40 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10971580" 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="#3" class="mim-tip-reference" title="Faccio, L., Fusco, C., Chen, A., Martinotti, S., Bonventre, J. V., Zervos, A. S. <strong>Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia.</strong> J. Biol. Chem. 275: 2581-2588, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644717</a>] [<a href="https://doi.org/10.1074/jbc.275.4.2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644717">Faccio et al. (2000)</a> isolated a cDNA encoding PRSS25, which they called OMI. The C terminus of OMI has extensive homology to HTRA, but unlike HTRA, which is secreted, OMI is localized in the endoplasmic reticulum. The OMI protein has several novel putative protein-protein interaction motifs, as well as a PDZ domain and an Src homology 3-binding domain. Northern blot analysis revealed that OMI is ubiquitously expressed as a major 2.1-kb transcript and a minor 4.5-kb transcript; highest expression was in placenta and pancreas. Among tumor cell lines, high expression of OMI was found in promyelocytic leukemia, chronic myelogenous leukemia, Burkitt lymphoma, and colorectal carcinoma lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644717" 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 immunofluorescence analysis of MCF-7 breast cancer cells and subfractionation of HEK293 cells, <a href="#7" class="mim-tip-reference" title="Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., Alnemri, E. S. <strong>Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction.</strong> J. Biol. Chem. 277: 432-438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11606597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11606597</a>] [<a href="https://doi.org/10.1074/jbc.M109721200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11606597">Hegde et al. (2002)</a> found that OMI colocalized with the caspase activator SMAC (DIABLO; <a href="/entry/605219">605219</a>) in the mitochondrial intermembrane space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11606597" 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 genomic sequence analysis, <a href="#4" class="mim-tip-reference" title="Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K. G., West, A., Savopoulos, J., Hassan, N. J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J. B., Dingwall, C., Livi, G. P., Creasy, C. L. <strong>Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response.</strong> Europ. J. Biochem. 267: 5699-5710, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10971580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10971580</a>] [<a href="https://doi.org/10.1046/j.1432-1327.2000.01589.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10971580">Gray et al. (2000)</a> determined that the HTRA2 gene contains 8 exons and spans 3.8 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10971580" 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 genomic sequence analysis, <a href="#4" class="mim-tip-reference" title="Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K. G., West, A., Savopoulos, J., Hassan, N. J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J. B., Dingwall, C., Livi, G. P., Creasy, C. L. <strong>Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response.</strong> Europ. J. Biochem. 267: 5699-5710, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10971580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10971580</a>] [<a href="https://doi.org/10.1046/j.1432-1327.2000.01589.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10971580">Gray et al. (2000)</a> mapped the HTRA2 gene to 2p13. <a href="#3" class="mim-tip-reference" title="Faccio, L., Fusco, C., Chen, A., Martinotti, S., Bonventre, J. V., Zervos, A. S. <strong>Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia.</strong> J. Biol. Chem. 275: 2581-2588, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644717</a>] [<a href="https://doi.org/10.1074/jbc.275.4.2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644717">Faccio et al. (2000)</a> mapped the OMI gene to 2p12 by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10971580+10644717" 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="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 1/3/2017."None>Gross (2017)</a> mapped the HTRA2 gene to chromosome 2p13.1 based on an alignment of the HTRA2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF184911" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF184911</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#4" class="mim-tip-reference" title="Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K. G., West, A., Savopoulos, J., Hassan, N. J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J. B., Dingwall, C., Livi, G. P., Creasy, C. L. <strong>Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response.</strong> Europ. J. Biochem. 267: 5699-5710, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10971580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10971580</a>] [<a href="https://doi.org/10.1046/j.1432-1327.2000.01589.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10971580">Gray et al. (2000)</a> found that HTRA2 was upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment. Biochemical characterization of HTRA2 showed it to be predominantly a nuclear protease that undergoes autoproteolysis. This proteolysis was abolished when the predicted active site serine residue was altered to alanine by site-directed mutagenesis. HTRA2 cleaved beta-casein (<a href="/entry/115460">115460</a>) with an inhibitor profile similar to that described for E. coli HtrA, in addition to an increase in beta-casein turnover when the assay temperature was raised from 37 to 45 degrees Celsius. The biochemical and sequence similarities between HTRA2 and its bacterial homologs, in conjunction with its nuclear location and upregulation in response to tunicamycin and heat shock, suggested that it is involved in mammalian stress response pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10971580" 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="#3" class="mim-tip-reference" title="Faccio, L., Fusco, C., Chen, A., Martinotti, S., Bonventre, J. V., Zervos, A. S. <strong>Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia.</strong> J. Biol. Chem. 275: 2581-2588, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644717</a>] [<a href="https://doi.org/10.1074/jbc.275.4.2581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644717">Faccio et al. (2000)</a> found that OMI interacted with MXI2, an alternatively spliced form of the p38 stress-activated kinase (<a href="/entry/600289">600289</a>). OMI protein, when made in a heterologous system, showed proteolytic activity against a nonspecific substrate beta-casein. The proteolytic activity of Omi was markedly upregulated in mouse kidney following ischemia/reperfusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644717" 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="Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R. <strong>A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.</strong> Molec. Cell 8: 613-621, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583623</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00341-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583623">Suzuki et al. (2001)</a> reported that HTRA2 is released from mitochondria and inhibits the function of XIAP (<a href="/entry/300079">300079</a>) by direct binding in a way similar to SMAC. Moreover, when overexpressed extramitochondrially, HTRA2 induced atypical cell death, which was neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP. A catalytically inactive mutant of HTRA2, however, did not induce cell death. <a href="#17" class="mim-tip-reference" title="Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R. <strong>A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.</strong> Molec. Cell 8: 613-621, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583623</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00341-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583623">Suzuki et al. (2001)</a> concluded that HTRA2 is a SMAC-like inhibitor of IAP (inhibitor of apoptosis proteins) activity with a serine protease-dependent cell death-inducing activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583623" 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 the baculoviral inhibitor of apoptosis repeat-3 (BIR3) domain of human XIAP in a yeast 2-hybrid screen, <a href="#7" class="mim-tip-reference" title="Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., Alnemri, E. S. <strong>Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction.</strong> J. Biol. Chem. 277: 432-438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11606597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11606597</a>] [<a href="https://doi.org/10.1074/jbc.M109721200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11606597">Hegde et al. (2002)</a> independently identified OMI as an XIAP-interacting protein. Removal of the mitochondrial targeting signal of OMI revealed an N-terminal AVPS motif at residue 134 for direct interaction of mature OMI with full-length cytosolic XIAP. Mature OMI also interacted with CIAP1 (BIRC2; <a href="/entry/601712">601712</a>) and CIAP2 (BIRC3; <a href="/entry/601721">601721</a>), but not with SMAC. Staurosporin-induced apoptosis in human Jurkat and HL-60 cells resulted in relocalization of OMI from mitochondria to the cytosol, similar to that observed for cytochrome c (<a href="/entry/123970">123970</a>) and SMAC. Overexpression of OMI in HeLa cells did not induce apoptosis, but it sensitized cells to staurosporin-induced apoptosis. Conversely, knockdown of OMI in HeLa or MCF-7 cells reduced cell sensitivity to staurosporin. Mutation analysis suggested that OMI induced apoptosis by interacting with XIAP via its AVPS motif, thereby disrupting the inhibitory interaction between XIAP and caspase-9 (CASP9; <a href="/entry/602234">602234</a>). OMI showed an additional proapoptotic function that was independent of XIAP binding but dependent upon its serine protease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11606597" 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="Jin, S., Kalkum, M., Overholtzer, M., Stoffel, A., Chait, B. T., Levine, A. J. <strong>CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals.</strong> Genes Dev. 17: 359-367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569127[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.1047003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12569127">Jin et al. (2003)</a> determined that the apoptosis inhibitor CIAP1 was degraded in a p53 (TP53; <a href="/entry/191170">191170</a>)-dependent manner by HTRA2 following induction of apoptosis in primary mouse thymocytes and HeLa cells. Northern blot analysis revealed that p53 induced expression of HTRA2. Treatment of mouse thymocytes with a serine protease inhibitor blocked p53-dependent CIAP1 degradation and apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12569127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Trencia, A., Fiory, F., Maitan, M. A., Vito, P., Barbagallo, A. P. M., Perfetti, A., Miele, C., Ungaro, P., Oriente, F., Cilenti, L., Zervos, A. S., Formisano, P., Beguinot, F. <strong>Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.</strong> J. Biol. Chem. 279: 46566-46572, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328349</a>] [<a href="https://doi.org/10.1074/jbc.M406317200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15328349">Trencia et al. (2004)</a> determined that the protease-dependent proapoptotic function of human OMI resulted from proteolytic degradation of cytosolic PEA15 (<a href="/entry/603434">603434</a>), a 15-kD protein with broad antiapoptotic function. OMI did not coprecipitate with PEA15 from HeLa cells under normal conditions. However, exposure of cells to ultraviolet C radiation resulted in cytosolic relocalization of OMI, interaction of OMI with PEA15, and PEA15 degradation. Pharmacologic inhibition of OMI serine protease activity or overexpression of PEA15 reduced cell sensitivity to ultraviolet C. <a href="#18" class="mim-tip-reference" title="Trencia, A., Fiory, F., Maitan, M. A., Vito, P., Barbagallo, A. P. M., Perfetti, A., Miele, C., Ungaro, P., Oriente, F., Cilenti, L., Zervos, A. S., Formisano, P., Beguinot, F. <strong>Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.</strong> J. Biol. Chem. 279: 46566-46572, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328349</a>] [<a href="https://doi.org/10.1074/jbc.M406317200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15328349">Trencia et al. (2004)</a> concluded that the caspase-independent cell death induced by cytoplasmic release of OMI is mediated by PEA15 degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15328349" 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="#11" class="mim-tip-reference" title="Liu, M.-J., Liu, M.-L., Shen, Y.-F., Kim, J.-M., Lee, B.-H., Lee, Y.-S., Hong, S.-T. <strong>Transgenic mice with neuron-specific overexpression of HtrA2/Omi suggest a neuroprotective role for HtrA2/Omi.</strong> Biochem. Biophys. Res. Commun. 362: 295-300, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17707776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17707776</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.07.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17707776">Liu et al. (2007)</a> found that transgenic mice overexpressing human HTRA2 in neurons were indistinguishable from wildtype in development, health, behavior, or reproductive ability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17707776" 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="Chao, J.-R., Parganas, E., Boyd, K., Hong, C. Y., Opferman, J. T., Ihle, J. N. <strong>Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.</strong> Nature 452: 98-102, 2008. Note: Erratum: Nature 452: 900 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18288109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18288109</a>] [<a href="https://doi.org/10.1038/nature06604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18288109">Chao et al. (2008)</a> demonstrated that a BCL2 (<a href="/entry/151430">151430</a>) family-related protein, HAX1 (<a href="/entry/605998">605998</a>), is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of HAX1 with the mitochondrial proteases PARL (<a href="/entry/607858">607858</a>) and HTRA2. These interactions allow HAX1 to present HTRA2 to PARL, and thereby facilitate the processing of HTRA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed Htra2 prevented the accumulation of mitochondrial outer membrane-associated activated Bax (<a href="/entry/600040">600040</a>), an event that initiates apoptosis. Together, <a href="#2" class="mim-tip-reference" title="Chao, J.-R., Parganas, E., Boyd, K., Hong, C. Y., Opferman, J. T., Ihle, J. N. <strong>Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.</strong> Nature 452: 98-102, 2008. Note: Erratum: Nature 452: 900 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18288109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18288109</a>] [<a href="https://doi.org/10.1038/nature06604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18288109">Chao et al. (2008)</a> concluded that their results identified a previously unknown sequence of interactions involving a Bcl2 family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18288109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Radke, S., Chander, H., Schafer, P., Meiss, G., Kruger, R., Schulz, J. B., Germain, D. <strong>Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi.</strong> J. Biol. Chem. 283: 12681-12685, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18362145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18362145</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18362145[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/10.1074/jbc.C800036200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18362145">Radke et al. (2008)</a> reported that the proteasome has a major role in ubiquitin-dependent quality control of proteins targeted for the mitochondrial inner membrane. They found that inhibition of the proteasome in HEK293T cells resulted in accumulation of mitochondrial intermembrane proteins. Inhibition of proteasome function also resulted in upregulated OMI expression and OMI-dependent degradation of mitochondrial intermembrane endonuclease G (ENDOG; <a href="/entry/600440">600440</a>). <a href="#14" class="mim-tip-reference" title="Radke, S., Chander, H., Schafer, P., Meiss, G., Kruger, R., Schulz, J. B., Germain, D. <strong>Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi.</strong> J. Biol. Chem. 283: 12681-12685, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18362145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18362145</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18362145[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/10.1074/jbc.C800036200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18362145">Radke et al. (2008)</a> concluded that OMI may represent a second checkpoint in mitochondrial protein quality control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18362145" 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>Parkinson Disease 13, Autosomal Dominant, Susceptibility to</em></strong></p><p>
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In 2 unrelated Taiwanese patients with Parkinson disease (PARK13; <a href="/entry/610297">610297</a>), <a href="#10" class="mim-tip-reference" title="Lin, C.-H., Chen, M.-L., Chen, G. S., Tai, C.-H., Wu, R.-M. <strong>Novel variant pro143ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria.</strong> Hum. Genet. 130: 817-827, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21701785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21701785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21701785[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/10.1007/s00439-011-1041-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21701785">Lin et al. (2011)</a> identified a heterozygous 427C-G transversion in the HTRA2 gene, resulting in a pro143-to-ala (P143A) substitution in a highly conserved region between the IAP-binding motif and the serine protease domain. One of the patients was identified from a cohort of 133 patients with early-onset or familial PD and the other from a cohort of 390 patients with late-onset sporadic PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21701785" 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>Two variants in the HTRA2 gene identified in patients with PD by <a href="#16" class="mim-tip-reference" title="Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. <strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong> Hum. Molec. Genet. 14: 2099-2111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>] [<a href="https://doi.org/10.1093/hmg/ddi215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961413">Strauss et al. (2005)</a> have been reclassified as variants of unknown significance. <a href="#16" class="mim-tip-reference" title="Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. <strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong> Hum. Molec. Genet. 14: 2099-2111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>] [<a href="https://doi.org/10.1093/hmg/ddi215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961413">Strauss et al. (2005)</a> performed a mutation screening of the HTRA2 gene in German patients with Parkinson disease. Four of 518 patients were heterozygous for a G399S mutation (<a href="#0001">606441.0001</a>), which was absent in 370 healthy controls. A novel A141S polymorphism (<a href="#0002">606441.0002</a>) was also associated with PD (p less than 0.05). Both mutations resulted in defective activation of the protease activity of HTRA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that the S399 mutant HTRA2 and to a lesser extent the S141 allele induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing the S399 mutant HTRA2 were more susceptible to stress-induced cell death than wildtype cells. Moreover, HTRA2 was detected in pathognomonic Lewy bodies in brains of idiopathic PD patients. The authors hypothesized that mitochondrial dysfunction may underlie the neurodegeneration seen in some patients with PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961413" 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="Simon-Sanchez, J., Singleton, A. B. <strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong> Hum. Molec. Genet. 17: 1988-1993, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364387</a>] [<a href="https://doi.org/10.1093/hmg/ddn096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364387">Simon-Sanchez and Singleton (2008)</a>, however, failed to find an association between the G399S or A141S variants and PD among 644 PD patients and 828 controls; in addition, no associations were observed after stratifying by age. <a href="#15" class="mim-tip-reference" title="Simon-Sanchez, J., Singleton, A. B. <strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong> Hum. Molec. Genet. 17: 1988-1993, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364387</a>] [<a href="https://doi.org/10.1093/hmg/ddn096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364387">Simon-Sanchez and Singleton (2008)</a> concluded that variability at HTRA2 does not contribute to risk of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364387" 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>3-Methylglutaconic Aciduria Type VIII</em></strong></p><p>
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In 3 infant sibs, born of consanguineous parents of Druze origin, and in an unrelated male infant, born of consanguineous parents of Ashkenazi Jewish descent, with 3-methylglutaconic aciduria type VIII (MGCA8; <a href="/entry/617248">617248</a>), <a href="#12" class="mim-tip-reference" title="Mandel, H., Saita, S., Edvardson, S., Jalas, C., Shaag, A., Goldsher, D., Vlodavsky, E., Langer, T., Elpeleg, O. <strong>Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 53: 690-696, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208207</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208207">Mandel et al. (2016)</a> identified homozygous mutations in the HTRA2 gene (<a href="#0004">606441.0004</a> and <a href="#0005">606441.0005</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the protein. Patient fibroblasts showed increased sensitivity to apoptotic insults which could be restored by expression of the wildtype protein and by expression of a proteolytically inactive variant. The impaired cell growth of patient cells could only be rescued by a proteolytically active protein, suggesting different roles for the chaperone and inherent protease activity of HTRA2. Patient skeletal muscle showed abnormal mitochondrial morphology with disturbed cristae, but fibroblasts showed normal mitochondrial tubular and reticulated networks, suggesting tissue-specific effects of loss of HTRA2. Mitochondrial respiratory function was normal in patient cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27208207" 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, born of consanguineous Mexican parents, with MGCA8, <a href="#13" class="mim-tip-reference" title="Olahova, M., Thompson, K. Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M.-E., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W. <strong>Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.</strong> J. Inherit. Metab. Dis. 40: 121-130, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27696117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27696117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27696117[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/10.1007/s10545-016-9977-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27696117">Olahova et al. (2017)</a> identified homozygous mutations in the HTRA2 gene (<a href="#0006">606441.0006</a> and <a href="#0007">606441.0007</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Fibroblasts and/or skeletal muscle samples from the proband in each family showed undetectable levels of HTRA2, but the steady-state levels of mitochondrial oxidative phosphorylation subunits and complexes were not significantly affected compared to controls. Cells from 1 of the patients showed increased proteolytic processing of OPA1 (<a href="/entry/605290">605290</a>), which is involved in mitochondrial fission and fusion; however, there was not a major impact on mitochondrial morphology, network, ultrastructure, or oxidative phosphorylation subunits. Patient fibroblasts were more susceptible to apoptotic insults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27696117" 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>The mouse mutant mnd2 (motor neuron degeneration-2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages. <a href="#9" class="mim-tip-reference" title="Jones, J. M., Datta, P., Srinivasula, S. M., Ji, W., Gupta, S., Zhang, Z., Davies, E., Hajnoczky, G., Saunders, T. L., Van Keuren, M. L., Fernandes-Alnemri, T., Meisler, M. H., Alnemri, E. S. <strong>Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice.</strong> Nature 425: 721-727, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14534547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14534547</a>] [<a href="https://doi.org/10.1038/nature02052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14534547">Jones et al. (2003)</a> identified the mnd2 mutation as the missense mutation ser276 to cys (S276C) in the protease domain of the nuclear-encoded mitochondrial serine protease Omi. Protease activity of Omi was greatly reduced in tissues of mnd2 mice but was restored in mice rescued by a bacterial artificial chromosome transgene containing the wildtype Omi gene. Deletion of the PDZ domain partially restored protease activity to the inactive recombinant Omi protein carrying the S276C mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increased the susceptibility of mitochondria to induction of the permeability transition, and increased the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. <a href="#9" class="mim-tip-reference" title="Jones, J. M., Datta, P., Srinivasula, S. M., Ji, W., Gupta, S., Zhang, Z., Davies, E., Hajnoczky, G., Saunders, T. L., Van Keuren, M. L., Fernandes-Alnemri, T., Meisler, M. H., Alnemri, E. S. <strong>Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice.</strong> Nature 425: 721-727, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14534547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14534547</a>] [<a href="https://doi.org/10.1038/nature02052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14534547">Jones et al. (2003)</a> concluded that neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14534547" 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> rs72470545 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72470545;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/rs72470545?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=rs72470545" 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=rs72470545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by <a href="#6" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/26/2019."None>Hamosh (2019)</a>.</p><p>In 4 patients with Parkinson disease from a sample of 518 German patients, <a href="#16" class="mim-tip-reference" title="Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. <strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong> Hum. Molec. Genet. 14: 2099-2111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>] [<a href="https://doi.org/10.1093/hmg/ddi215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961413">Strauss et al. (2005)</a> identified a heterozygous 1195G-A transition in exon 7 of the HTRA2 gene, predicting a substitution of serine for glycine at codon 399 (G399S). The mutation was not found among 370 control samples. In transfected cells, the mutation caused mitochondrial dysfunction and altered morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961413" 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 direct sequencing, <a href="#15" class="mim-tip-reference" title="Simon-Sanchez, J., Singleton, A. B. <strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong> Hum. Molec. Genet. 17: 1988-1993, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364387</a>] [<a href="https://doi.org/10.1093/hmg/ddn096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364387">Simon-Sanchez and Singleton (2008)</a> found a similar frequency of the G399S allele among 644 PD patients (0.77%) and 828 controls (0.72%); the difference was not statistically significant. No association was observed after stratifying by age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364387" 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="#6" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/26/2019."None>Hamosh (2019)</a> noted that the G399S variant was found in 1,069 of 282,850 alleles and in 8 homozygotes in the gnomAD database (December 26, 2019), calling into question the pathogenicity of the variant.</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> rs72470544 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72470544;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/rs72470544?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=rs72470544" 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=rs72470544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by <a href="#6" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/26/2019."None>Hamosh (2019)</a>.</p><p>In a sample of 518 German patients with Parkinson disease, <a href="#16" class="mim-tip-reference" title="Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. <strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong> Hum. Molec. Genet. 14: 2099-2111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>] [<a href="https://doi.org/10.1093/hmg/ddi215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961413">Strauss et al. (2005)</a> identified a heterozygous 421G-T transversion in exon 1 of the HTRA2 gene that resulted in a change from alanine to serine at position 141 of the peptide sequence (A141S). In an association study using the A141S polymorphism in 414 Parkinson disease patients and 331 healthy controls, the authors identified 26 heterozygous individuals in the patient group (6.2%) and 10 heterozygous individuals in the control group (3%). No homozygous carriers of the mutation were observed. Thus, <a href="#16" class="mim-tip-reference" title="Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. <strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong> Hum. Molec. Genet. 14: 2099-2111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>] [<a href="https://doi.org/10.1093/hmg/ddi215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961413">Strauss et al. (2005)</a> found a significant overrepresentation of carriers of the T allele (S141) in patients compared with controls (chi square = 4.25, P = 0.039, odds ratio = 2.15, CI = 1.02-4.52). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961413" 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="Bogaerts, V., Nuytemans, K., Reumers, J., Pals, P., Engelborghs, S., Pickut, B., Corsmit, E., Peeters, K., Schymkowitz, J., De Deyn, P. P., Cras, P., Rousseau, F., Theuns, J., Van Broeckhoven, C. <strong>Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease.</strong> Hum. Mutat. 29: 832-840, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18401856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18401856</a>] [<a href="https://doi.org/10.1002/humu.20713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18401856">Bogaerts et al. (2008)</a> found a similar frequency of the A141S substitution among 266 Belgian patients with Parkinson disease and 359 controls (2.85% and 2.37%, respectively); the difference was not statistically significant. Furthermore, the A141S substitution did not occur at a highly conserved residue. The findings cast into doubt the pathogenicity of the variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18401856" 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="Simon-Sanchez, J., Singleton, A. B. <strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong> Hum. Molec. Genet. 17: 1988-1993, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364387</a>] [<a href="https://doi.org/10.1093/hmg/ddn096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364387">Simon-Sanchez and Singleton (2008)</a> also failed to find an association between the A141S variant and PD among 644 PD patients and 828 controls; in addition, no association was observed after stratifying by age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364387" 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="#6" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/26/2019."None>Hamosh (2019)</a> noted that the A141S variant was found in 4,958 of 261,768 alleles and in 67 homozygotes in the gnomAD database (December 26, 2019), calling into question the pathogenicity of the variant.</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> rs387906942 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906942;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/rs387906942?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=rs387906942" 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=rs387906942" 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=RCV000023546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023546</a>
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<p>In 2 unrelated Taiwanese patients with Parkinson disease (PARK13; <a href="/entry/610297">610297</a>), <a href="#10" class="mim-tip-reference" title="Lin, C.-H., Chen, M.-L., Chen, G. S., Tai, C.-H., Wu, R.-M. <strong>Novel variant pro143ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria.</strong> Hum. Genet. 130: 817-827, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21701785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21701785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21701785[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/10.1007/s00439-011-1041-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21701785">Lin et al. (2011)</a> identified a heterozygous 427C-G transversion in the HTRA2 gene, resulting in a pro143-to-ala (P143A) substitution in a highly conserved region between the IAP-binding motif and the serine protease domain. One of the patients was identified from a cohort of 133 patients with early-onset or familial PD and the other from a cohort of 390 patients with late-onset sporadic PD. The mutation was also found in 2 sibs of the patient with early-onset PD; the sibs did not have a movement disorder, but 1 had hyposmia at age 71 years. The mutation was not found in 850 controls. In vitro functional expression studies in primary dopaminergic cells showed that the P143A protein caused neurite degeneration. In addition, cells containing the P143A variant showed increased mitochondrial dysfunction and apoptosis upon exposure to rotenone compared to cells with wildtype HTRA2. Cells with the mutant protein also contained higher levels of phosphorylated HTRA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21701785" 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> rs767006508 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767006508;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/rs767006508?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=rs767006508" 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=rs767006508" 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=RCV000412669 OR RCV002523896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412669, RCV002523896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412669...</a>
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<p>In 3 infant sibs, born of consanguineous parents of Druze origin with 3-methylglutaconic aciduria type VIII (MGCA8; <a href="/entry/617248">617248</a>), <a href="#12" class="mim-tip-reference" title="Mandel, H., Saita, S., Edvardson, S., Jalas, C., Shaag, A., Goldsher, D., Vlodavsky, E., Langer, T., Elpeleg, O. <strong>Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 53: 690-696, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208207</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208207">Mandel et al. (2016)</a> identified a homozygous c.1211G-A transition (c.1211G-A, NM_013247) at the last nucleotide of exon 7 of the HTRA2 gene, predicted to result in an arg404-to-gln (R404Q) substitution. However, the mutation also causes a splicing defect, resulting in the skipping of exon 7 and an in-frame deletion of 32 residues (Ser372_His403). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database (February 2016). Western blot analysis of patient cells showed complete absence of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27208207" 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">rs1057519080 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519080;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=rs1057519080" 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=rs1057519080" 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=RCV000412533" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412533" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412533</a>
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<p>In a male infant, born of consanguineous parents of Ashkenazi Jewish descent, with 3-methylglutaconic aciduria type VIII (MGCA8; <a href="/entry/617248">617248</a>), <a href="#12" class="mim-tip-reference" title="Mandel, H., Saita, S., Edvardson, S., Jalas, C., Shaag, A., Goldsher, D., Vlodavsky, E., Langer, T., Elpeleg, O. <strong>Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 53: 690-696, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208207</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208207">Mandel et al. (2016)</a> identified a homozygous 5-bp deletion (c.1312_1316del, NM_013247) in the HTRA2 gene, resulting in a frameshift and premature termination (Ala438fs). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database (February 2016) or in about 700 Ashkenazi Jewish control exomes. Western blot analysis of patient cells showed complete absence of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27208207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIII</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">rs1057519081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519081;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=rs1057519081" 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=rs1057519081" 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=RCV000412614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412614</a>
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<p>In a boy, born of consanguineous Pakistani parents, with 3-methylglutaconic aciduria type VIII (MGCA8; <a href="/entry/617248">617248</a>), <a href="#13" class="mim-tip-reference" title="Olahova, M., Thompson, K. Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M.-E., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W. <strong>Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.</strong> J. Inherit. Metab. Dis. 40: 121-130, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27696117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27696117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27696117[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/10.1007/s10545-016-9977-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27696117">Olahova et al. (2017)</a> identified a homozygous G-to-C transversion in intron 3 (c.906+1G-C, NM_013247) of the HTRA2 gene, resulting in a splicing defect. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the unaffected parents were heterozygous for the mutation, but DNA from an affected sib was not tested. Analysis of patient cells showed 2 aberrant transcripts: one with an in-frame deletion of 42 amino acids (Gly261_Asp302del) and another with the inclusion of 34 residues followed by a termination codon (Asp302_Phe303insTer35). Patient cells showed undetectable levels of HTRA2 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27696117" 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">rs1057519082 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519082;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=rs1057519082" 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=rs1057519082" 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=RCV000412483" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412483" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412483</a>
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<p>In 2 sibs, born of consanguineous Mexican parents, with 3-methylglutaconic aciduria type VIII (MGCA8; <a href="/entry/617248">617248</a>), <a href="#13" class="mim-tip-reference" title="Olahova, M., Thompson, K. Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M.-E., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W. <strong>Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.</strong> J. Inherit. Metab. Dis. 40: 121-130, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27696117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27696117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27696117[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/10.1007/s10545-016-9977-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27696117">Olahova et al. (2017)</a> identified a homozygous c.728_730delinsCAT (c.728_730delinsCAT, NM_013247) mutation in the HTRA2 gene, resulting in a Leu243_Pro244delinsProSer substitution within a highly conserved peptidase domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; parental DNA was not available for segregation analysis. Patient cells showed undetectable levels of HTRA2 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27696117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1038/nature06604" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.275.4.2581" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10971580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10971580</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10971580" 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/10.1046/j.1432-1327.2000.01589.x" target="_blank">Full Text</a>]
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Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., Alnemri, E. S.
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[<a href="https://doi.org/10.1074/jbc.M109721200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.1047003" target="_blank">Full Text</a>]
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Jones, J. M., Datta, P., Srinivasula, S. M., Ji, W., Gupta, S., Zhang, Z., Davies, E., Hajnoczky, G., Saunders, T. L., Van Keuren, M. L., Fernandes-Alnemri, T., Meisler, M. H., Alnemri, E. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14534547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14534547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14534547" 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/nature02052" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-011-1041-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2007.07.118" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27208207" 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-2016-103922" target="_blank">Full Text</a>]
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Olahova, M., Thompson, K. Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M.-E., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W.
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<strong>Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.</strong>
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J. Inherit. Metab. Dis. 40: 121-130, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27696117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27696117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27696117[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=27696117" 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/s10545-016-9977-2" target="_blank">Full Text</a>]
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Radke, S., Chander, H., Schafer, P., Meiss, G., Kruger, R., Schulz, J. B., Germain, D.
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<strong>Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18362145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18362145</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18362145[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=18362145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.C800036200" target="_blank">Full Text</a>]
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<a id="Simon-Sanchez2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simon-Sanchez, J., Singleton, A. B.
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<strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong>
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Hum. Molec. Genet. 17: 1988-1993, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364387</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364387" 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/ddn096" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Strauss2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R.
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<strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong>
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Hum. Molec. Genet. 14: 2099-2111, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961413</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961413" 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/ddi215" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Suzuki2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R.
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<strong>A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.</strong>
|
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Molec. Cell 8: 613-621, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583623</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583623" 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/s1097-2765(01)00341-0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Trencia2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trencia, A., Fiory, F., Maitan, M. A., Vito, P., Barbagallo, A. P. M., Perfetti, A., Miele, C., Ungaro, P., Oriente, F., Cilenti, L., Zervos, A. S., Formisano, P., Beguinot, F.
|
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<strong>Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.</strong>
|
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J. Biol. Chem. 279: 46566-46572, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15328349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M406317200" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/03/2017
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/14/2016<br>Patricia A. Hartz - updated : 11/21/2012<br>Cassandra L. Kniffin - updated : 4/12/2012<br>Ada Hamosh - updated : 5/9/2008<br>George E. Tiller - updated : 8/4/2006<br>Ada Hamosh - updated : 10/29/2003
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 11/6/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/26/2019
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/20/2017<br>mgross : 01/03/2017<br>carol : 12/17/2016<br>carol : 12/16/2016<br>ckniffin : 12/14/2016<br>alopez : 04/21/2015<br>mgross : 12/11/2012<br>terry : 11/21/2012<br>carol : 4/12/2012<br>ckniffin : 4/12/2012<br>ckniffin : 11/17/2010<br>ckniffin : 11/16/2010<br>alopez : 8/18/2008<br>terry : 7/25/2008<br>alopez : 5/19/2008<br>terry : 5/9/2008<br>mgross : 1/12/2007<br>mgross : 1/12/2007<br>carol : 11/22/2006<br>alopez : 8/4/2006<br>alopez : 8/4/2006<br>alopez : 10/30/2003<br>terry : 10/29/2003<br>mgross : 11/7/2001<br>mgross : 11/6/2001<br>mgross : 11/6/2001
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606441
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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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HTRA SERINE PEPTIDASE 2; HTRA2
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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HTRA, E. COLI, HOMOLOG OF, 2<br />
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PROTEASE, SERINE, 25; PRSS25<br />
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OMI
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HTRA2</em></strong>
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</span>
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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: 2p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:74,529,405-74,533,556 </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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<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="2">
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<span class="mim-font">
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2p13.1
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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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{Parkinson disease 13}
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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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610297
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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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3-methylglutaconic aciduria, type VIII
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</td>
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<td>
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<span class="mim-font">
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617248
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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</table>
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<br />
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<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 HTRA2 gene encodes a serine protease that localizes to the mitochondrial intermembrane space. Following apoptotic stimuli, HTRA2 can expose an inhibitor of apoptosis protein (IAP) binding motif, thus mediating cell death, or can mediate cell death via its serine protease activity (Suzuki et al., 2001). </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>Using presenilin-1 (104311) as bait in a yeast 2-hybrid screen of fetal brain cDNA, Gray et al. (2000) isolated a cDNA encoding PRSS25, which they called HTRA2. By screening an adult brain cDNA library, they obtained 3 different splice variants of HTRA2. The predominant HTRA2 variant encodes a 458-amino acid protein. HTRA2 shows extensive homology to the E. coli HtrA genes, which are essential for bacterial survival at high temperatures. HTRA2 is also homologous to HTRA1 (PRSS11; 602194), which is differentially expressed in human osteoarthritic cartilage and after SV40 transformation of human fibroblasts. The HTRA2 protein is 85% identical to its mouse homolog. Northern blot analysis detected a major 1.9-kb HTRA2 transcript in all tissues tested, with highest levels in heart and skeletal muscle and variable distribution in brain regions. In human cell lines, HTRA2 was present as 2 polypeptides of 38 and 40 kD. </p><p>Faccio et al. (2000) isolated a cDNA encoding PRSS25, which they called OMI. The C terminus of OMI has extensive homology to HTRA, but unlike HTRA, which is secreted, OMI is localized in the endoplasmic reticulum. The OMI protein has several novel putative protein-protein interaction motifs, as well as a PDZ domain and an Src homology 3-binding domain. Northern blot analysis revealed that OMI is ubiquitously expressed as a major 2.1-kb transcript and a minor 4.5-kb transcript; highest expression was in placenta and pancreas. Among tumor cell lines, high expression of OMI was found in promyelocytic leukemia, chronic myelogenous leukemia, Burkitt lymphoma, and colorectal carcinoma lines. </p><p>By immunofluorescence analysis of MCF-7 breast cancer cells and subfractionation of HEK293 cells, Hegde et al. (2002) found that OMI colocalized with the caspase activator SMAC (DIABLO; 605219) in the mitochondrial intermembrane space. </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">
|
|
<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">
|
|
<p>By genomic sequence analysis, Gray et al. (2000) determined that the HTRA2 gene contains 8 exons and spans 3.8 kb. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>By genomic sequence analysis, Gray et al. (2000) mapped the HTRA2 gene to 2p13. Faccio et al. (2000) mapped the OMI gene to 2p12 by FISH. </p><p>Gross (2017) mapped the HTRA2 gene to chromosome 2p13.1 based on an alignment of the HTRA2 sequence (GenBank AF184911) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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">
|
|
<p>Gray et al. (2000) found that HTRA2 was upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment. Biochemical characterization of HTRA2 showed it to be predominantly a nuclear protease that undergoes autoproteolysis. This proteolysis was abolished when the predicted active site serine residue was altered to alanine by site-directed mutagenesis. HTRA2 cleaved beta-casein (115460) with an inhibitor profile similar to that described for E. coli HtrA, in addition to an increase in beta-casein turnover when the assay temperature was raised from 37 to 45 degrees Celsius. The biochemical and sequence similarities between HTRA2 and its bacterial homologs, in conjunction with its nuclear location and upregulation in response to tunicamycin and heat shock, suggested that it is involved in mammalian stress response pathways. </p><p>Faccio et al. (2000) found that OMI interacted with MXI2, an alternatively spliced form of the p38 stress-activated kinase (600289). OMI protein, when made in a heterologous system, showed proteolytic activity against a nonspecific substrate beta-casein. The proteolytic activity of Omi was markedly upregulated in mouse kidney following ischemia/reperfusion. </p><p>Suzuki et al. (2001) reported that HTRA2 is released from mitochondria and inhibits the function of XIAP (300079) by direct binding in a way similar to SMAC. Moreover, when overexpressed extramitochondrially, HTRA2 induced atypical cell death, which was neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP. A catalytically inactive mutant of HTRA2, however, did not induce cell death. Suzuki et al. (2001) concluded that HTRA2 is a SMAC-like inhibitor of IAP (inhibitor of apoptosis proteins) activity with a serine protease-dependent cell death-inducing activity. </p><p>Using the baculoviral inhibitor of apoptosis repeat-3 (BIR3) domain of human XIAP in a yeast 2-hybrid screen, Hegde et al. (2002) independently identified OMI as an XIAP-interacting protein. Removal of the mitochondrial targeting signal of OMI revealed an N-terminal AVPS motif at residue 134 for direct interaction of mature OMI with full-length cytosolic XIAP. Mature OMI also interacted with CIAP1 (BIRC2; 601712) and CIAP2 (BIRC3; 601721), but not with SMAC. Staurosporin-induced apoptosis in human Jurkat and HL-60 cells resulted in relocalization of OMI from mitochondria to the cytosol, similar to that observed for cytochrome c (123970) and SMAC. Overexpression of OMI in HeLa cells did not induce apoptosis, but it sensitized cells to staurosporin-induced apoptosis. Conversely, knockdown of OMI in HeLa or MCF-7 cells reduced cell sensitivity to staurosporin. Mutation analysis suggested that OMI induced apoptosis by interacting with XIAP via its AVPS motif, thereby disrupting the inhibitory interaction between XIAP and caspase-9 (CASP9; 602234). OMI showed an additional proapoptotic function that was independent of XIAP binding but dependent upon its serine protease activity. </p><p>Jin et al. (2003) determined that the apoptosis inhibitor CIAP1 was degraded in a p53 (TP53; 191170)-dependent manner by HTRA2 following induction of apoptosis in primary mouse thymocytes and HeLa cells. Northern blot analysis revealed that p53 induced expression of HTRA2. Treatment of mouse thymocytes with a serine protease inhibitor blocked p53-dependent CIAP1 degradation and apoptosis. </p><p>Trencia et al. (2004) determined that the protease-dependent proapoptotic function of human OMI resulted from proteolytic degradation of cytosolic PEA15 (603434), a 15-kD protein with broad antiapoptotic function. OMI did not coprecipitate with PEA15 from HeLa cells under normal conditions. However, exposure of cells to ultraviolet C radiation resulted in cytosolic relocalization of OMI, interaction of OMI with PEA15, and PEA15 degradation. Pharmacologic inhibition of OMI serine protease activity or overexpression of PEA15 reduced cell sensitivity to ultraviolet C. Trencia et al. (2004) concluded that the caspase-independent cell death induced by cytoplasmic release of OMI is mediated by PEA15 degradation. </p><p>Liu et al. (2007) found that transgenic mice overexpressing human HTRA2 in neurons were indistinguishable from wildtype in development, health, behavior, or reproductive ability. </p><p>Chao et al. (2008) demonstrated that a BCL2 (151430) family-related protein, HAX1 (605998), is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of HAX1 with the mitochondrial proteases PARL (607858) and HTRA2. These interactions allow HAX1 to present HTRA2 to PARL, and thereby facilitate the processing of HTRA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed Htra2 prevented the accumulation of mitochondrial outer membrane-associated activated Bax (600040), an event that initiates apoptosis. Together, Chao et al. (2008) concluded that their results identified a previously unknown sequence of interactions involving a Bcl2 family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting. </p><p>Radke et al. (2008) reported that the proteasome has a major role in ubiquitin-dependent quality control of proteins targeted for the mitochondrial inner membrane. They found that inhibition of the proteasome in HEK293T cells resulted in accumulation of mitochondrial intermembrane proteins. Inhibition of proteasome function also resulted in upregulated OMI expression and OMI-dependent degradation of mitochondrial intermembrane endonuclease G (ENDOG; 600440). Radke et al. (2008) concluded that OMI may represent a second checkpoint in mitochondrial protein quality control. </p>
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</span>
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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>Parkinson Disease 13, Autosomal Dominant, Susceptibility to</em></strong></p><p>
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In 2 unrelated Taiwanese patients with Parkinson disease (PARK13; 610297), Lin et al. (2011) identified a heterozygous 427C-G transversion in the HTRA2 gene, resulting in a pro143-to-ala (P143A) substitution in a highly conserved region between the IAP-binding motif and the serine protease domain. One of the patients was identified from a cohort of 133 patients with early-onset or familial PD and the other from a cohort of 390 patients with late-onset sporadic PD. </p><p>Two variants in the HTRA2 gene identified in patients with PD by Strauss et al. (2005) have been reclassified as variants of unknown significance. Strauss et al. (2005) performed a mutation screening of the HTRA2 gene in German patients with Parkinson disease. Four of 518 patients were heterozygous for a G399S mutation (606441.0001), which was absent in 370 healthy controls. A novel A141S polymorphism (606441.0002) was also associated with PD (p less than 0.05). Both mutations resulted in defective activation of the protease activity of HTRA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that the S399 mutant HTRA2 and to a lesser extent the S141 allele induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing the S399 mutant HTRA2 were more susceptible to stress-induced cell death than wildtype cells. Moreover, HTRA2 was detected in pathognomonic Lewy bodies in brains of idiopathic PD patients. The authors hypothesized that mitochondrial dysfunction may underlie the neurodegeneration seen in some patients with PD. </p><p>Simon-Sanchez and Singleton (2008), however, failed to find an association between the G399S or A141S variants and PD among 644 PD patients and 828 controls; in addition, no associations were observed after stratifying by age. Simon-Sanchez and Singleton (2008) concluded that variability at HTRA2 does not contribute to risk of PD. </p><p><strong><em>3-Methylglutaconic Aciduria Type VIII</em></strong></p><p>
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In 3 infant sibs, born of consanguineous parents of Druze origin, and in an unrelated male infant, born of consanguineous parents of Ashkenazi Jewish descent, with 3-methylglutaconic aciduria type VIII (MGCA8; 617248), Mandel et al. (2016) identified homozygous mutations in the HTRA2 gene (606441.0004 and 606441.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the protein. Patient fibroblasts showed increased sensitivity to apoptotic insults which could be restored by expression of the wildtype protein and by expression of a proteolytically inactive variant. The impaired cell growth of patient cells could only be rescued by a proteolytically active protein, suggesting different roles for the chaperone and inherent protease activity of HTRA2. Patient skeletal muscle showed abnormal mitochondrial morphology with disturbed cristae, but fibroblasts showed normal mitochondrial tubular and reticulated networks, suggesting tissue-specific effects of loss of HTRA2. Mitochondrial respiratory function was normal in patient cells. </p><p>In 2 sibs, born of consanguineous Mexican parents, with MGCA8, Olahova et al. (2017) identified homozygous mutations in the HTRA2 gene (606441.0006 and 606441.0007). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Fibroblasts and/or skeletal muscle samples from the proband in each family showed undetectable levels of HTRA2, but the steady-state levels of mitochondrial oxidative phosphorylation subunits and complexes were not significantly affected compared to controls. Cells from 1 of the patients showed increased proteolytic processing of OPA1 (605290), which is involved in mitochondrial fission and fusion; however, there was not a major impact on mitochondrial morphology, network, ultrastructure, or oxidative phosphorylation subunits. Patient fibroblasts were more susceptible to apoptotic insults. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>The mouse mutant mnd2 (motor neuron degeneration-2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages. Jones et al. (2003) identified the mnd2 mutation as the missense mutation ser276 to cys (S276C) in the protease domain of the nuclear-encoded mitochondrial serine protease Omi. Protease activity of Omi was greatly reduced in tissues of mnd2 mice but was restored in mice rescued by a bacterial artificial chromosome transgene containing the wildtype Omi gene. Deletion of the PDZ domain partially restored protease activity to the inactive recombinant Omi protein carrying the S276C mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increased the susceptibility of mitochondria to induction of the permeability transition, and increased the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. Jones et al. (2003) concluded that neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HTRA2, GLY399SER
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<br />
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SNP: rs72470545,
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gnomAD: rs72470545,
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ClinVar: RCV000004589, RCV000891932
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2019).</p><p>In 4 patients with Parkinson disease from a sample of 518 German patients, Strauss et al. (2005) identified a heterozygous 1195G-A transition in exon 7 of the HTRA2 gene, predicting a substitution of serine for glycine at codon 399 (G399S). The mutation was not found among 370 control samples. In transfected cells, the mutation caused mitochondrial dysfunction and altered morphology. </p><p>By direct sequencing, Simon-Sanchez and Singleton (2008) found a similar frequency of the G399S allele among 644 PD patients (0.77%) and 828 controls (0.72%); the difference was not statistically significant. No association was observed after stratifying by age. </p><p>Hamosh (2019) noted that the G399S variant was found in 1,069 of 282,850 alleles and in 8 homozygotes in the gnomAD database (December 26, 2019), calling into question the pathogenicity of the variant.</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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HTRA2, ALA141SER
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<br />
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SNP: rs72470544,
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gnomAD: rs72470544,
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ClinVar: RCV000004590, RCV001516571, RCV002496256
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2019).</p><p>In a sample of 518 German patients with Parkinson disease, Strauss et al. (2005) identified a heterozygous 421G-T transversion in exon 1 of the HTRA2 gene that resulted in a change from alanine to serine at position 141 of the peptide sequence (A141S). In an association study using the A141S polymorphism in 414 Parkinson disease patients and 331 healthy controls, the authors identified 26 heterozygous individuals in the patient group (6.2%) and 10 heterozygous individuals in the control group (3%). No homozygous carriers of the mutation were observed. Thus, Strauss et al. (2005) found a significant overrepresentation of carriers of the T allele (S141) in patients compared with controls (chi square = 4.25, P = 0.039, odds ratio = 2.15, CI = 1.02-4.52). </p><p>Bogaerts et al. (2008) found a similar frequency of the A141S substitution among 266 Belgian patients with Parkinson disease and 359 controls (2.85% and 2.37%, respectively); the difference was not statistically significant. Furthermore, the A141S substitution did not occur at a highly conserved residue. The findings cast into doubt the pathogenicity of the variant. </p><p>Simon-Sanchez and Singleton (2008) also failed to find an association between the A141S variant and PD among 644 PD patients and 828 controls; in addition, no association was observed after stratifying by age. </p><p>Hamosh (2019) noted that the A141S variant was found in 4,958 of 261,768 alleles and in 67 homozygotes in the gnomAD database (December 26, 2019), calling into question the pathogenicity of the variant.</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 PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, 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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HTRA2, PRO143ALA
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<br />
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SNP: rs387906942,
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gnomAD: rs387906942,
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ClinVar: RCV000023546
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated Taiwanese patients with Parkinson disease (PARK13; 610297), Lin et al. (2011) identified a heterozygous 427C-G transversion in the HTRA2 gene, resulting in a pro143-to-ala (P143A) substitution in a highly conserved region between the IAP-binding motif and the serine protease domain. One of the patients was identified from a cohort of 133 patients with early-onset or familial PD and the other from a cohort of 390 patients with late-onset sporadic PD. The mutation was also found in 2 sibs of the patient with early-onset PD; the sibs did not have a movement disorder, but 1 had hyposmia at age 71 years. The mutation was not found in 850 controls. In vitro functional expression studies in primary dopaminergic cells showed that the P143A protein caused neurite degeneration. In addition, cells containing the P143A variant showed increased mitochondrial dysfunction and apoptosis upon exposure to rotenone compared to cells with wildtype HTRA2. Cells with the mutant protein also contained higher levels of phosphorylated HTRA2. </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 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIII</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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HTRA2, ARG404GLN
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<br />
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SNP: rs767006508,
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gnomAD: rs767006508,
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ClinVar: RCV000412669, RCV002523896
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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 3 infant sibs, born of consanguineous parents of Druze origin with 3-methylglutaconic aciduria type VIII (MGCA8; 617248), Mandel et al. (2016) identified a homozygous c.1211G-A transition (c.1211G-A, NM_013247) at the last nucleotide of exon 7 of the HTRA2 gene, predicted to result in an arg404-to-gln (R404Q) substitution. However, the mutation also causes a splicing defect, resulting in the skipping of exon 7 and an in-frame deletion of 32 residues (Ser372_His403). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database (February 2016). Western blot analysis of patient cells showed complete absence of 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>.0005 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIII</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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HTRA2, 5-BP DEL, 1312
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<br />
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SNP: rs1057519080,
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ClinVar: RCV000412533
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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 male infant, born of consanguineous parents of Ashkenazi Jewish descent, with 3-methylglutaconic aciduria type VIII (MGCA8; 617248), Mandel et al. (2016) identified a homozygous 5-bp deletion (c.1312_1316del, NM_013247) in the HTRA2 gene, resulting in a frameshift and premature termination (Ala438fs). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database (February 2016) or in about 700 Ashkenazi Jewish control exomes. Western blot analysis of patient cells showed complete absence of 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>.0006 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIII</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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HTRA2, IVS3DS, G-C, +1
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<br />
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SNP: rs1057519081,
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ClinVar: RCV000412614
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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 boy, born of consanguineous Pakistani parents, with 3-methylglutaconic aciduria type VIII (MGCA8; 617248), Olahova et al. (2017) identified a homozygous G-to-C transversion in intron 3 (c.906+1G-C, NM_013247) of the HTRA2 gene, resulting in a splicing defect. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the unaffected parents were heterozygous for the mutation, but DNA from an affected sib was not tested. Analysis of patient cells showed 2 aberrant transcripts: one with an in-frame deletion of 42 amino acids (Gly261_Asp302del) and another with the inclusion of 34 residues followed by a termination codon (Asp302_Phe303insTer35). Patient cells showed undetectable levels of HTRA2 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 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIII</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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HTRA2, 3-BP DEL/INS, NT728
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<br />
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SNP: rs1057519082,
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ClinVar: RCV000412483
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 sibs, born of consanguineous Mexican parents, with 3-methylglutaconic aciduria type VIII (MGCA8; 617248), Olahova et al. (2017) identified a homozygous c.728_730delinsCAT (c.728_730delinsCAT, NM_013247) mutation in the HTRA2 gene, resulting in a Leu243_Pro244delinsProSer substitution within a highly conserved peptidase domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; parental DNA was not available for segregation analysis. Patient cells showed undetectable levels of HTRA2 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>REFERENCES</strong>
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</span>
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</h4>
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Bogaerts, V., Nuytemans, K., Reumers, J., Pals, P., Engelborghs, S., Pickut, B., Corsmit, E., Peeters, K., Schymkowitz, J., De Deyn, P. P., Cras, P., Rousseau, F., Theuns, J., Van Broeckhoven, C.
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<strong>Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease.</strong>
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Hum. Mutat. 29: 832-840, 2008.
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[PubMed: 18401856]
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[Full Text: https://doi.org/10.1002/humu.20713]
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<li>
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Chao, J.-R., Parganas, E., Boyd, K., Hong, C. Y., Opferman, J. T., Ihle, J. N.
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<strong>Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.</strong>
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Nature 452: 98-102, 2008. Note: Erratum: Nature 452: 900 only, 2008.
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[PubMed: 18288109]
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[Full Text: https://doi.org/10.1038/nature06604]
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</p>
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<li>
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<p class="mim-text-font">
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Faccio, L., Fusco, C., Chen, A., Martinotti, S., Bonventre, J. V., Zervos, A. S.
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<strong>Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia.</strong>
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J. Biol. Chem. 275: 2581-2588, 2000.
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[PubMed: 10644717]
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[Full Text: https://doi.org/10.1074/jbc.275.4.2581]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K. G., West, A., Savopoulos, J., Hassan, N. J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J. B., Dingwall, C., Livi, G. P., Creasy, C. L.
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<strong>Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response.</strong>
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Europ. J. Biochem. 267: 5699-5710, 2000.
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[PubMed: 10971580]
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[Full Text: https://doi.org/10.1046/j.1432-1327.2000.01589.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 1/3/2017.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 12/26/2019.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., Alnemri, E. S.
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<strong>Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction.</strong>
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J. Biol. Chem. 277: 432-438, 2002.
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[PubMed: 11606597]
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[Full Text: https://doi.org/10.1074/jbc.M109721200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jin, S., Kalkum, M., Overholtzer, M., Stoffel, A., Chait, B. T., Levine, A. J.
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<strong>CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals.</strong>
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Genes Dev. 17: 359-367, 2003.
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[PubMed: 12569127]
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[Full Text: https://doi.org/10.1101/gad.1047003]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jones, J. M., Datta, P., Srinivasula, S. M., Ji, W., Gupta, S., Zhang, Z., Davies, E., Hajnoczky, G., Saunders, T. L., Van Keuren, M. L., Fernandes-Alnemri, T., Meisler, M. H., Alnemri, E. S.
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<strong>Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice.</strong>
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Nature 425: 721-727, 2003.
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[PubMed: 14534547]
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[Full Text: https://doi.org/10.1038/nature02052]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lin, C.-H., Chen, M.-L., Chen, G. S., Tai, C.-H., Wu, R.-M.
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<strong>Novel variant pro143ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria.</strong>
|
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Hum. Genet. 130: 817-827, 2011.
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[PubMed: 21701785]
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[Full Text: https://doi.org/10.1007/s00439-011-1041-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Liu, M.-J., Liu, M.-L., Shen, Y.-F., Kim, J.-M., Lee, B.-H., Lee, Y.-S., Hong, S.-T.
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<strong>Transgenic mice with neuron-specific overexpression of HtrA2/Omi suggest a neuroprotective role for HtrA2/Omi.</strong>
|
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Biochem. Biophys. Res. Commun. 362: 295-300, 2007.
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[PubMed: 17707776]
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[Full Text: https://doi.org/10.1016/j.bbrc.2007.07.118]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mandel, H., Saita, S., Edvardson, S., Jalas, C., Shaag, A., Goldsher, D., Vlodavsky, E., Langer, T., Elpeleg, O.
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<strong>Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria.</strong>
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J. Med. Genet. 53: 690-696, 2016.
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[PubMed: 27208207]
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[Full Text: https://doi.org/10.1136/jmedgenet-2016-103922]
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</p>
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<li>
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<p class="mim-text-font">
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Olahova, M., Thompson, K. Hardy, S. A., Barbosa, I. A., Besse, A., Anagnostou, M.-E., White, K., Davey, T., Simpson, M. A., Champion, M., Enns, G., Schelley, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A., McFarland, R., Deshpande, C., Bonnen, P. E., Taylor, R. W.
|
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<strong>Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.</strong>
|
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J. Inherit. Metab. Dis. 40: 121-130, 2017.
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[PubMed: 27696117]
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[Full Text: https://doi.org/10.1007/s10545-016-9977-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Radke, S., Chander, H., Schafer, P., Meiss, G., Kruger, R., Schulz, J. B., Germain, D.
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<strong>Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi.</strong>
|
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J. Biol. Chem. 283: 12681-12685, 2008.
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[PubMed: 18362145]
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[Full Text: https://doi.org/10.1074/jbc.C800036200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Simon-Sanchez, J., Singleton, A. B.
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<strong>Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls.</strong>
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Hum. Molec. Genet. 17: 1988-1993, 2008.
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[PubMed: 18364387]
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[Full Text: https://doi.org/10.1093/hmg/ddn096]
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</p>
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<li>
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<p class="mim-text-font">
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Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R.
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<strong>Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.</strong>
|
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Hum. Molec. Genet. 14: 2099-2111, 2005.
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[PubMed: 15961413]
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[Full Text: https://doi.org/10.1093/hmg/ddi215]
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</p>
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<li>
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<p class="mim-text-font">
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Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R.
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<strong>A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.</strong>
|
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Molec. Cell 8: 613-621, 2001.
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[PubMed: 11583623]
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[Full Text: https://doi.org/10.1016/s1097-2765(01)00341-0]
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<li>
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<p class="mim-text-font">
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Trencia, A., Fiory, F., Maitan, M. A., Vito, P., Barbagallo, A. P. M., Perfetti, A., Miele, C., Ungaro, P., Oriente, F., Cilenti, L., Zervos, A. S., Formisano, P., Beguinot, F.
|
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<strong>Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.</strong>
|
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J. Biol. Chem. 279: 46566-46572, 2004.
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[PubMed: 15328349]
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[Full Text: https://doi.org/10.1074/jbc.M406317200]
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