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Entry
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- *602194 - HTRA SERINE PEPTIDASE 1; HTRA1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602194</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602194">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000166033;t=ENST00000368984" 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=5654" 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=602194" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000166033;t=ENST00000368984" 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_002775" 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_002775" 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=602194" 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=03725&isoform_id=03725_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/HTRA1" 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/1513059,1621244,3777617,4506141,5281519,18202620,116283290,119569697,119569698,158261201,193787240,193787351" 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/Q92743" 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=5654" 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=ENSG00000166033;t=ENST00000368984" 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=HTRA1" 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=HTRA1" 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+5654" 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/HTRA1" 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:5654" 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/5654" 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=chr10&hgg_gene=ENST00000368984.8&hgg_start=122461553&hgg_end=122514907&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/htra1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602194[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=602194[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/ENSG00000166033" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=HTRA1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=HTRA1" 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=HTRA1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HTRA1&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/PA33829" 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:9476" 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:1929076" 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/HTRA1#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:1929076" 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/5654/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=5654" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040704-64" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=HTRA1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703219008<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602194
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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 1; HTRA1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HtrA, E. COLI, HOMOLOG OF; HTRA<br />
|
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PROTEASE, SERINE, 11; PRSS11
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HTRA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HTRA1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/10/624?start=-3&limit=10&highlight=624">10q26.13</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:122461553-122514907&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'})">10:122,461,553-122,514,907</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=610149,610149,600142,616779" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/10/624?start=-3&limit=10&highlight=624">
|
|
10q26.13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Macular degeneration, age-related, 7}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610149"> 610149 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
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|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Macular degeneration, age-related, neovascular type}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610149"> 610149 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
CARASIL syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/600142"> 600142 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616779"> 616779 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>HTRA1 is a member of the HTRA (high temperature requirement) family of serine proteases first identified in bacteria. These proteases are characterized by a highly conserved trypsin (see <a href="/entry/276000">276000</a>)-like serine protease domain and at least 1 C-terminal PDZ domain. HTRA1 also contains an insulin-like growth factor-binding protein (see <a href="/entry/146730">146730</a>) domain and a Kazal-type serine protease inhibitor (see <a href="/entry/167790">167790</a>) motif at its N terminus. HTRA1 can degrade several extracellular matrix components and plays a role in cancer and degenerative diseases (summary by <a href="#11" class="mim-tip-reference" title="Grau, S., Richards, P. J., Kerr, B., Hughes, C., Caterson, B., Williams, A. S., Junker, U., Jones, S. A., Clausen, T., Ehrmann, M. <strong>The role of human HtrA1 in arthritic disease.</strong> J. Biol. Chem. 281: 6124-6129, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377621</a>] [<a href="https://doi.org/10.1074/jbc.M500361200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377621">Grau et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16377621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#23" class="mim-tip-reference" title="Zumbrunn, J., Trueb, B. <strong>Primary structure of a putative serine protease specific for IGF-binding proteins.</strong> FEBS Lett. 398: 187-192, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977104</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01229-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8977104">Zumbrunn and Trueb (1996)</a> cloned the cDNA for a human protein, termed L56 by them, that seemed to be part of the IGF signaling system. The predicted protein encodes a 480-amino acid polypeptide with a molecular mass of 51 kD. <a href="#23" class="mim-tip-reference" title="Zumbrunn, J., Trueb, B. <strong>Primary structure of a putative serine protease specific for IGF-binding proteins.</strong> FEBS Lett. 398: 187-192, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977104</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01229-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8977104">Zumbrunn and Trueb (1996)</a> found that PRSS11 contains a secretory signal sequence, an IGFBP-binding domain, and a serine protease domain. The serine protease domain is most similar to certain bacterial serine proteases. By Northern blot analysis, <a href="#23" class="mim-tip-reference" title="Zumbrunn, J., Trueb, B. <strong>Primary structure of a putative serine protease specific for IGF-binding proteins.</strong> FEBS Lett. 398: 187-192, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977104</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01229-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8977104">Zumbrunn and Trueb (1996)</a> showed that PRSS11 is expressed in a variety of human tissues, with strongest expression in placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8977104" 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="Hu, S.-I., Carozza, M., Klein, M., Nantermet, P., Luk, D., Crowl, R. M. <strong>Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage.</strong> J. Biol. Chem. 273: 34406-34412, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9852107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9852107</a>] [<a href="https://doi.org/10.1074/jbc.273.51.34406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9852107">Hu et al. (1998)</a> also cloned PRSS11. The deduced 480-amino acid protein is 98% identical to the cow, guinea pig, and rabbit proteins. It contains an N terminus homologous to MAC25 (IGFBP7; <a href="/entry/602867">602867</a>) with a conserved Kazal-type serine protease inhibitor motif, as well as a C-terminal PDZ domain. Semiquantitative RT-PCR and immunoblot analyses showed an approximately 7-fold increase of PRSS11 in osteoarthritis cartilage compared with controls. Functional and mutational analyses indicated that PRS11 is a serine protease dependent on the presence of a serine at position 328. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9852107" 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 in situ hybridization, <a href="#16" class="mim-tip-reference" title="Kato, T., Manabe, R. I., Igarashi, H., Kametani, F., Hirokawa, S., Sekine, Y., Fujita, N., Saito, S., Kawashima, Y., Hatano, Y., Ando, S., Nozaki, H., and 18 others. <strong>Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.</strong> J. Clin. Invest. 131: e140555, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34779414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34779414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34779414[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/10.1172/JCI140555" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34779414">Kato et al. (2021)</a> showed that Htra1 was expressed in endothelial cells of pial arteries in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34779414" 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 fluorescence in situ hybridization, <a href="#24" class="mim-tip-reference" title="Zumbrunn, J., Trueb, B. <strong>Localization of the gene for a serine protease with IGF-binding domain (PRSS11) to human chromosome 10q25.3-q26.2.</strong> Genomics 45: 461-462, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9344681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9344681</a>] [<a href="https://doi.org/10.1006/geno.1997.4953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9344681">Zumbrunn and Trueb (1997)</a> mapped the PRSS11 gene to chromosome 10q25.3-q26.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9344681" 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="#12" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 8/31/2022."None>Gross (2022)</a> mapped the HTRA1 gene to chromosome 10q26.13 based on an alignment of the HTRA1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC011352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC011352</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#6" class="mim-tip-reference" title="Chien, J., Staub, J., Hu, S.-I., Erickson-Johnson, M. R., Couch, F. J., Smith, D. I., Crowl, R. M., Kaufmann, S. H., Shridhar, V. <strong>A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer.</strong> Oncogene 23: 1636-1644, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716297</a>] [<a href="https://doi.org/10.1038/sj.onc.1207271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716297">Chien et al. (2004)</a> found that HTRA1 was downregulated in 59% of primary ovarian tumors and observed high frequencies for LOH at microsatellite markers near HTRA1 on 10q26. Antisense transfection studies showed that downregulation of HTRA1 promoted anchorage-independent growth, while exogenous expression induced cell death. <a href="#6" class="mim-tip-reference" title="Chien, J., Staub, J., Hu, S.-I., Erickson-Johnson, M. R., Couch, F. J., Smith, D. I., Crowl, R. M., Kaufmann, S. H., Shridhar, V. <strong>A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer.</strong> Oncogene 23: 1636-1644, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716297</a>] [<a href="https://doi.org/10.1038/sj.onc.1207271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716297">Chien et al. (2004)</a> suggested that HTRA1 may be a tumor suppressor involved in promoting serine-protease-mediated cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14716297" 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="Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V. <strong>Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.</strong> J. Clin. Invest. 116: 1994-2004, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16767218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16767218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[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/10.1172/JCI27698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16767218">Chien et al. (2006)</a> demonstrated that downregulation of HTRA1 in ovarian cancer cell lines attenuated cisplatin- and paclitaxel-induced cytotoxicity, whereas forced expression of HTRA1 enhanced chemotherapeutic cytotoxicity. Patients with ovarian epithelial (<a href="/entry/167000">167000</a>) or gastric (<a href="/entry/137215">137215</a>) tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. <a href="#5" class="mim-tip-reference" title="Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V. <strong>Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.</strong> J. Clin. Invest. 116: 1994-2004, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16767218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16767218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[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/10.1172/JCI27698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16767218">Chien et al. (2006)</a> suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16767218" 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 ELISA, <a href="#11" class="mim-tip-reference" title="Grau, S., Richards, P. J., Kerr, B., Hughes, C., Caterson, B., Williams, A. S., Junker, U., Jones, S. A., Clausen, T., Ehrmann, M. <strong>The role of human HtrA1 in arthritic disease.</strong> J. Biol. Chem. 281: 6124-6129, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377621</a>] [<a href="https://doi.org/10.1074/jbc.M500361200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377621">Grau et al. (2006)</a> found that expression of HTRA1 was upregulated in synovial fluid from both osteoarthritis (OA; see <a href="/entry/165720">165720</a>) and rheumatoid arthritis (RA; see <a href="/entry/180300">180300</a>) patients compared with normal human fluid. HTRA1 was also highly expressed in and secreted by cultured OA and RA synovial fibroblasts, but not by normal human foreskin fibroblasts. Recombinant human HTRA1 lacking the N-terminal IGF-binding and serine protease inhibitor domains, representing an autoproteolytically processed form, degraded purified human fibronectin (FN1; <a href="/entry/135600">135600</a>) into several fragments. Synovial fibroblasts exposed to these fragments subsequently upregulated mRNA expression and secretion of the matrix metalloproteases MMP1 (<a href="/entry/120353">120353</a>) and MMP3 (<a href="/entry/185250">185250</a>). Inhibition of HTRA1 abrogated fibronectin fragment formation and MMP upregulation. <a href="#11" class="mim-tip-reference" title="Grau, S., Richards, P. J., Kerr, B., Hughes, C., Caterson, B., Williams, A. S., Junker, U., Jones, S. A., Clausen, T., Ehrmann, M. <strong>The role of human HtrA1 in arthritic disease.</strong> J. Biol. Chem. 281: 6124-6129, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16377621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16377621</a>] [<a href="https://doi.org/10.1074/jbc.M500361200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16377621">Grau et al. (2006)</a> concluded that HTRA1 can contribute to destruction of extracellular matrix through both direct and indirect mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16377621" 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 quantitative RT-PCR analysis, <a href="#19" class="mim-tip-reference" title="Tiaden, A. N., Klawitter, M., Lux, V., Mirsaidi, A., Bahrenberg, G., Glanz, S., Quero, L., Liebscher, T., Wuertz, K., Ehrmann, M., Richards, P. J. <strong>Detrimental role for human high temperature requirement serine protease A1 (HTRA1) in the pathogenesis of intervertebral disc (IVD) degeneration.</strong> J. Biol. Chem. 287: 21335-21345, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22556410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22556410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22556410[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.M112.341032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22556410">Tiaden et al. (2012)</a> found that expression of HTRA1 was upregulated in degenerating patient intervertebral discs (IVDs), and expression of HTRA1 positively correlated with disease severity. Western blot analysis detected both full-length and processed HTRA1 species at apparent molecular masses of 50 and 42 kD, respectively. The 42-kD form was found in patient IVD samples only, and the amount increased with severity of disease. Cultured IVD fibroblasts exposed to recombinant HTRA1 lacking the N-terminal domains responded by increasing their expression of MMP1 and MMP3, as well as a specific subset of other matrix proteases. IVD cells exposed to HTRA1-generated fibronectin fragments also showed upregulation and activation of MMPs. This effect was not observed in cells exposed to inactivated truncated HTRA1 or following HTRA1 inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22556410" 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="Akhatib, B., Onnerfjord, P., Gawri, R., Ouellet, J., Jarzem, P., Heinegard, D., Mort, J., Roughley, P., Haglund, L. <strong>Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging.</strong> J. Biol. Chem. 288: 19280-19287, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23673665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23673665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23673665[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.M112.443010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23673665">Akhatib et al. (2013)</a> found that chondroadherin (CHAD; <a href="/entry/602178">602178</a>) was intact in normal human IVDs, but that it was fragmented in adults with IVD degeneration and in damaged discs in adolescent idiopathic scoliosis. The amount of fragmented CHAD correlated with severity of disease, but in all cases, CHAD was specifically cleaved between ile80 and tyr81. <a href="#1" class="mim-tip-reference" title="Akhatib, B., Onnerfjord, P., Gawri, R., Ouellet, J., Jarzem, P., Heinegard, D., Mort, J., Roughley, P., Haglund, L. <strong>Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging.</strong> J. Biol. Chem. 288: 19280-19287, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23673665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23673665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23673665[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.M112.443010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23673665">Akhatib et al. (2013)</a> found that the CHAD cleavage site generated by HTRA1 was identical to that present in situ. HTRA1 protein was observed in both degenerate adult and adolescent scoliotic samples and was elevated compared with normal disc samples. <a href="#1" class="mim-tip-reference" title="Akhatib, B., Onnerfjord, P., Gawri, R., Ouellet, J., Jarzem, P., Heinegard, D., Mort, J., Roughley, P., Haglund, L. <strong>Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging.</strong> J. Biol. Chem. 288: 19280-19287, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23673665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23673665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23673665[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.M112.443010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23673665">Akhatib et al. (2013)</a> concluded that HTRA1 plays a role in CHAD fragmentation in degenerating disc diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23673665" 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>Neonatal neutrophils fail to form neutrophil extracellular traps (NETs) due to circulating NET inhibitory peptides (NIPs), which are cleavage fragments of alpha-1-antitrypsin (A1AT, or SERPINA1; <a href="/entry/107400">107400</a>). Using immunofluorescence assays, <a href="#4" class="mim-tip-reference" title="Campbell, R. A., Campbell, H. D., Bircher, J. S., de Araujo, C. V., Denorme, F., Crandell, J. L., Rustad, J. L., Monts, J., Cody, M. J., Kosaka, Y., Yost, C. C. <strong>Placental HTRA1 cleaves alpha-1-antitrypsin to generate a NET-inhibitory peptide.</strong> Blood 138: 977-988, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34192300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34192300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34192300[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/10.1182/blood.2020009021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34192300">Campbell et al. (2021)</a> showed that human placenta from both term and preterm pregnancies secreted HTRA1 into fetal circulation. Plasma HTRA1 levels were reduced after delivery, and decreased HTRA1 plasma levels were associated with decreased levels of NIPs. Placental HTRA1 cleaved A1AT after amino acid 382 to generate a C-terminal cleavage fragment of A1AT, termed A1ATM383S-CF, that could inhibit NET formation in vitro. Through NET inhibition, A1ATM383S-CF decreased bacterial killing, but it maintained other key neutrophil activities in vitro. In vivo analysis with wildtype mice showed that mouse placenta also secreted Htra1, and placental Htra1 cleaved A1at to generate A1atM383S-CF and inhibit NET formation by neonatal neutrophils. Analysis with Htra1 -/- and wildtype mice revealed that inhibition of NET formation during experimental neonatal sepsis improved survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34192300" 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>Age-Related Macular Degeneration 7</em></strong></p><p>
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From a cohort of Southeast Asians in Hong Kong, <a href="#8" class="mim-tip-reference" title="DeWan, A., Liu, M., Hartman, S., Zhang, S. S.-M., Liu, D. T. L., Zhao, C., Tam, P. O. S., Chan, W. M., Lam, D. S. C., Snyder, M., Barnstable, C., Pang, C. P., Hoh, J. <strong>HTRA1 promoter polymorphism in wet age-related macular degeneration.</strong> Science 314: 989-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053108</a>] [<a href="https://doi.org/10.1126/science.1133807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053108">DeWan et al. (2006)</a> identified 96 patients who had been previously diagnosed with wet age-related macular degeneration (ARMD7; <a href="/entry/610149">610149</a>) and 138 matched control individuals who were ARMD-free. Because the putative locus on 10q26 in which a previously identified SNP with significant association with ARMD had been removed from GenBank (see LOC387715, <a href="/entry/611313">611313</a>), <a href="#8" class="mim-tip-reference" title="DeWan, A., Liu, M., Hartman, S., Zhang, S. S.-M., Liu, D. T. L., Zhao, C., Tam, P. O. S., Chan, W. M., Lam, D. S. C., Snyder, M., Barnstable, C., Pang, C. P., Hoh, J. <strong>HTRA1 promoter polymorphism in wet age-related macular degeneration.</strong> Science 314: 989-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053108</a>] [<a href="https://doi.org/10.1126/science.1133807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053108">DeWan et al. (2006)</a> sequenced the entire local genomic region, including promoters, exons, and intron-exon junctions of PLEKHA1 (<a href="/entry/607772">607772</a>) and HTRA1, in search of the functional variant. They found that 1 SNP in the promoter region of HTRA1, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> (<a href="#0001">602194.0001</a>), located 512 base pairs upstream of the HTRA1 putative transcriptional start site and 6,096 basepairs downstream of the previously identified SNP, exhibited a complete linkage disequilibrium pattern with the previously identified SNP. The SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> resides within putative binding sites for the transcription factors adaptor-related protein complex 2-alpha (AP2-alpha; <a href="/entry/107580">107580</a>) and serum response factor (SRF; <a href="/entry/600589">600589</a>). Preliminary results showed higher HTRA1 expression correlated with the risk (AA) compared with the wildtype (GG) genotype in in vitro transfection assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17053108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., DeWan, A., Harmon, J., Bernstein, P. S., Shridhar, V., Zabriskie, N. A., Hoh, J., Howes, K., Zhang, K. <strong>A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.</strong> Science 314: 992-993, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053109</a>] [<a href="https://doi.org/10.1126/science.1133811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053109">Yang et al. (2006)</a> independently identified the same SNP in the HTRA1 promoter region as causative of age-related macular degeneration in a Caucasian cohort in Utah. The authors suggested that the estimated population-attributable risk for the SNP is 49.3%. Consistent with an additive effect, the estimated population-attributable risk from a joint model with CFH Y402H (<a href="/entry/134370#0008">134370.0008</a>) (i.e., for a risk allele at either locus) is 71.4%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17053109" 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>Contrary to the findings of <a href="#8" class="mim-tip-reference" title="DeWan, A., Liu, M., Hartman, S., Zhang, S. S.-M., Liu, D. T. L., Zhao, C., Tam, P. O. S., Chan, W. M., Lam, D. S. C., Snyder, M., Barnstable, C., Pang, C. P., Hoh, J. <strong>HTRA1 promoter polymorphism in wet age-related macular degeneration.</strong> Science 314: 989-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053108</a>] [<a href="https://doi.org/10.1126/science.1133807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053108">DeWan et al. (2006)</a> and <a href="#21" class="mim-tip-reference" title="Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., DeWan, A., Harmon, J., Bernstein, P. S., Shridhar, V., Zabriskie, N. A., Hoh, J., Howes, K., Zhang, K. <strong>A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.</strong> Science 314: 992-993, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053109</a>] [<a href="https://doi.org/10.1126/science.1133811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053109">Yang et al. (2006)</a>, <a href="#15" class="mim-tip-reference" title="Kanda, A., Chen, W., Othman, M., Branham, K. E. H., Brooks, M., Khanna, R., He, S., Lyons, R., Abecasis, G. R., Swaroop, A. <strong>A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration.</strong> Proc. Nat. Acad. Sci. 104: 16227-16232, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884985</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17884985[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0703933104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884985">Kanda et al. (2007)</a> found that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> had no significant impact on HTRA1 promoter activity in 3 different cells lines, and that HTRA1 mRNA expression exhibited no significant change between control and ARMD retinas. By evaluating 45 tag SNPs spanning the HTRA1, PLEKHA1, and LOC387715 in 466 cases of ARMD and 280 controls, they determined that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10490924;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10490924</a> in the LOC387715 gene alone, or a variant in strong linkage disequilibrium, could explain the bulk of the association between the 10q26 region and ARMD, whereas <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> in the HTRA1 gene could not. They concluded that the association of the HTRA1 polymorphism with ARMD susceptibility was likely to be indirect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17053109+17053108+17884985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a resequencing study of the locus on chromosome 10q26 associated with ARMD, <a href="#10" class="mim-tip-reference" title="Fritsche, L. G., Loenhardt, T., Janssen, A., Fisher, S. A., Rivera, A., Keilhauer, C. N., Weber, B. H. F. <strong>Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA.</strong> Nature Genet. 40: 892-896, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511946</a>] [<a href="https://doi.org/10.1038/ng.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511946">Fritsche et al. (2008)</a> identified an insertion/deletion polymorphism in the LOC387715 gene (<a href="/entry/611313#0002">611313.0002</a>) that was highly associated with ARMD and that generated an unstable mRNA. The authors also confirmed association of the SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> and identified an intronic SNP that they considered 'unlikely to exert consequences on gene function.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18511946" 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>Autosomal Recessive Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy</em></strong></p><p>
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Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>) is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. By linkage analysis and fine mapping, followed by candidate gene sequencing, in 6 consanguineous Japanese families with CARASIL, <a href="#13" class="mim-tip-reference" title="Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others. <strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong> New Eng. J. Med. 360: 1729-1739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19387015</a>] [<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19387015">Hara et al. (2009)</a> identified 4 different homozygous mutations in the HTRA1 gene (<a href="#0002">602194.0002</a>-<a href="#0005">602194.0005</a>). The mutant proteins were unable to repress TGF-beta (<a href="/entry/190180">190180</a>) activity, and increased expression TGFB1 was observed in the tunica media of affected small arteries. These findings indicated that CARASIL is a disease associated with dysregulation of TGF-beta signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19387015" 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>Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Type 2</em></strong></p><p>
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Using whole-exome sequencing to identify candidate genes in a family with autosomal dominant small vessel disease (cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2; CADASIL2; <a href="/entry/616779">616779</a>) in which known small vessel disease genes had been excluded, <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> identified heterozygosity for a missense mutation (R166L; <a href="#0001">602194.0001</a>) in the HTRA1 gene in all affected members. The mutation was not present in the 1000 Genomes Project and the EVS databases. The authors subsequently used high-throughput multiplex polymerase chain reaction and next-generation sequencing to screen all candidate genes in 201 unrelated probands from families with small vessel disease of unknown etiology. Ten of the probands (4.97%) harbored a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (p = 4.2 x 10(-6); odds ratio = 15.4; 95% CI = 4.9 - 45.5), strongly suggesting causality. In vitro activity analysis of HTRA1 mutants demonstrated a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 3,853 unrelated patients with cerebral small vessel disease, <a href="#7" class="mim-tip-reference" title="Coste, T., Herve, D., Neau, J. P., Jouvent, E., Ba, F., Bergametti, F., Lamy, M., Cogez, J., Derache, N., Schneckenburger, R., Grelet, M., Gollion, C., and 12 others. <strong>Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.</strong> Brain 144: 2616-2624, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34270682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34270682</a>] [<a href="https://doi.org/10.1093/brain/awab271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34270682">Coste et al. (2021)</a> identified 20 patients with heterozygous mutations in the HTRA1 gene leading to a premature stop codon, including 8 nonsense, 7 frameshift, and 2 canonical splice site mutations. This represented a highly significant enrichment of stop codon mutations in the HTRA1 gene compared to what was reported in control population databases, including the 1000 Genomes Project (in which no stop mutations were reported), gnomAD (v.3.1.1), and TOPmed (freeze 5) databases. RNA was available for 8 of the patients, and RT-PCR followed by Sanger sequencing analysis was consistent with nonsense-mediated decay of the mutant allele. <a href="#7" class="mim-tip-reference" title="Coste, T., Herve, D., Neau, J. P., Jouvent, E., Ba, F., Bergametti, F., Lamy, M., Cogez, J., Derache, N., Schneckenburger, R., Grelet, M., Gollion, C., and 12 others. <strong>Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.</strong> Brain 144: 2616-2624, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34270682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34270682</a>] [<a href="https://doi.org/10.1093/brain/awab271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34270682">Coste et al. (2021)</a> concluded that heterozygous mutations in the HTRA1 gene leading to a premature stop are a cause of CADASIL2. Clinical features of the patients with nonsense mutations in the HTRA1 gene were not different from other patients with CADASIL2, other than a likely lower penetrance, as only 61% of the patients had an affected relative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34270682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Francis, P. J., Appukuttan, B., Simmons, E., Landauer, N., Stoddard, J., Hamon, S., Ott, J., Ferguson, B., Klein, M., Stout, J. T., Neuringer, M. <strong>Rhesus monkeys and humans share common susceptibility genes for age-related macular diseases.</strong> Hum. Molec. Genet. 17: 2673-2680, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18535016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18535016</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18535016[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18535016">Francis et al. (2008)</a> genotyped 137 unrelated rhesus macaques, 81 with and 56 without macular drusen, and identified a variant in the Htra1 gene that was significantly associated with affected status. Functional analysis of the polymorphic variant showed a 2-fold increase in gene expression, supporting a role in pathogenesis. <a href="#9" class="mim-tip-reference" title="Francis, P. J., Appukuttan, B., Simmons, E., Landauer, N., Stoddard, J., Hamon, S., Ott, J., Ferguson, B., Klein, M., Stout, J. T., Neuringer, M. <strong>Rhesus monkeys and humans share common susceptibility genes for age-related macular diseases.</strong> Hum. Molec. Genet. 17: 2673-2680, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18535016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18535016</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18535016[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18535016">Francis et al. (2008)</a> stated that this was the first evidence that humans and macaques share the same genetic susceptibility factors for common complex disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18535016" 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="#22" class="mim-tip-reference" title="Zhang, L., Lim, S. L., Du, H., Zhang, M., Kozak, I., Hannum, G., Wang, X., Ouyang, H., Hughes, G., Zhao, L., Zhu, X., Lee, C., and 12 others. <strong>High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-beta family member growth differentiation factor 6.</strong> J. Biol. Chem. 287: 1520-1526, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22049084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22049084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22049084[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.M111.275990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22049084">Zhang et al. (2012)</a> found that Htra1 -/- mice showed reduced retinal vasculature compared with wildtype. Knockout of Htra1 significantly upregulated expression of Gdf6 (<a href="/entry/601147">601147</a>) and downregulated expression of Vegf (<a href="/entry/192240">192240</a>) in retinal pigment epithelia. Increased levels of phosphorylated Smad1 (<a href="/entry/601595">601595</a>), Smad5 (<a href="/entry/603110">603110</a>), and Smad8 (SMAD9; <a href="/entry/603295">603295</a>), which are downstream effectors of Gdf6 signaling, were present in Htra1 -/- brain. <a href="#22" class="mim-tip-reference" title="Zhang, L., Lim, S. L., Du, H., Zhang, M., Kozak, I., Hannum, G., Wang, X., Ouyang, H., Hughes, G., Zhao, L., Zhu, X., Lee, C., and 12 others. <strong>High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-beta family member growth differentiation factor 6.</strong> J. Biol. Chem. 287: 1520-1526, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22049084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22049084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22049084[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.M111.275990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22049084">Zhang et al. (2012)</a> concluded that HTRA1 regulates angiogenesis via TGF-beta signaling by GDF6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22049084" 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="#16" class="mim-tip-reference" title="Kato, T., Manabe, R. I., Igarashi, H., Kametani, F., Hirokawa, S., Sekine, Y., Fujita, N., Saito, S., Kawashima, Y., Hatano, Y., Ando, S., Nozaki, H., and 18 others. <strong>Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.</strong> J. Clin. Invest. 131: e140555, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34779414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34779414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34779414[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/10.1172/JCI140555" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34779414">Kato et al. (2021)</a> found that Htra1 -/- mice had normal blood pressure, blood glucose levels, and vascular density in brain parenchyma, with no motor deficits, white matter lesions, or ischemic lesions. However, Htra1 -/- mice exhibited accumulation of matrisome proteins, which are components of the extracellular matrix, in pial arteries and arterioles, recapitulating features of patients with CARASIL. Administration of candesartan, an angiotensin II type-1 receptor (AGTR1; <a href="/entry/106165">106165</a>) inhibitor, ameliorated accumulation of matrisome proteins and prevented vascular remodeling and decreased cerebral blood flow in Htra1 -/- mice, but it failed to prevent alterations in smooth muscle cells and pericytes. Furthermore, RNA-sequencing analysis showed that candesartan reduced expression of Fn1 (<a href="/entry/135600">135600</a>), Ltbp4 (<a href="/entry/604710">604710</a>), and Adamtsl2 (<a href="/entry/612277">612277</a>), which are involved in forming the extracellular matrix network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34779414" 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> rs11200638 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;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/rs11200638?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=rs11200638" 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=rs11200638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#8" class="mim-tip-reference" title="DeWan, A., Liu, M., Hartman, S., Zhang, S. S.-M., Liu, D. T. L., Zhao, C., Tam, P. O. S., Chan, W. M., Lam, D. S. C., Snyder, M., Barnstable, C., Pang, C. P., Hoh, J. <strong>HTRA1 promoter polymorphism in wet age-related macular degeneration.</strong> Science 314: 989-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053108</a>] [<a href="https://doi.org/10.1126/science.1133807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053108">DeWan et al. (2006)</a> identified a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a>) for which homozygosity for the AA genotype results in a 10-fold (confidence intervals 4.38 to 22.82) increased risk of wet age-related macular degeneration (see ARMD7, <a href="/entry/610149">610149</a>) in a Southeast Asian population identified in Hong Kong. <a href="#21" class="mim-tip-reference" title="Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., DeWan, A., Harmon, J., Bernstein, P. S., Shridhar, V., Zabriskie, N. A., Hoh, J., Howes, K., Zhang, K. <strong>A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.</strong> Science 314: 992-993, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053109</a>] [<a href="https://doi.org/10.1126/science.1133811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053109">Yang et al. (2006)</a> independently identified this variant as conferring risk in a Caucasian cohort from Utah. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17053109+17053108" 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="Mori, K., Horie-Inoue, K., Kohda, M., Kawasaki, I., Gehlbach, P. L., Awata, T., Yoneya, S., Okazaki, Y., Inoue, S. <strong>Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population.</strong> J. Hum. Genet. 52: 636-641, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17568988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17568988</a>] [<a href="https://doi.org/10.1007/s10038-007-0162-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17568988">Mori et al. (2007)</a> found a significant association between the -512A allele and ARMD among 123 Japanese patients and 133 Japanese controls. The frequency of the risk A allele was 0.577 and 0.380 in patients and controls, respectively, yielding an odds ratio of 2.23 (p = 7.75 x 10(-6)). The results were more significant in a subset of 104 Japanese patients with wet ARMD (p = 5.96 x 10(-7)). The association was significant in both nonsmokers and smokers, and was more significant in nonsmokers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17568988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Fritsche, L. G., Loenhardt, T., Janssen, A., Fisher, S. A., Rivera, A., Keilhauer, C. N., Weber, B. H. F. <strong>Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA.</strong> Nature Genet. 40: 892-896, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511946</a>] [<a href="https://doi.org/10.1038/ng.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511946">Fritsche et al. (2008)</a> identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> as 1 of 6 highly correlated risk alleles residing on a single risk haplotype within the 23.3-kb region on chromosome 10q26 associated with age-related macular degeneration (P = 6.9 x 10(-29)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18511946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 without ARMD acting as controls, <a href="#2" class="mim-tip-reference" title="Bergeron-Sawitzke, J., Gold, B., Olsh, A., Schlotterbeck, S., Lemon, K., Visvanathan, K., Allikmets, R., Dean, M. <strong>Multilocus analysis of age-related macular degeneration.</strong> Europ. J. Hum. Genet. 17: 1190-1199, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19259132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19259132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19259132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.23" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19259132">Bergeron-Sawitzke et al. (2009)</a> confirmed association between ARMD and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a>, with both the GA (OR, 3.2; p = 8.7 x 10(-9)) and AA (OR, 9.1; p = 6.4 x 10(-10)) genotypes. <a href="#2" class="mim-tip-reference" title="Bergeron-Sawitzke, J., Gold, B., Olsh, A., Schlotterbeck, S., Lemon, K., Visvanathan, K., Allikmets, R., Dean, M. <strong>Multilocus analysis of age-related macular degeneration.</strong> Europ. J. Hum. Genet. 17: 1190-1199, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19259132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19259132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19259132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.23" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19259132">Bergeron-Sawitzke et al. (2009)</a> noted that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11200638;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11200638</a> is in strong linkage disequilibrium with the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10490924;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10490924</a> SNP (<a href="/entry/611313#0001">611313.0001</a>) in the LOC387715 gene that has also been associated with ARMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19259132" 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>.0002 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113993971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993971;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/rs113993971?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=rs113993971" 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=rs113993971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), <a href="#13" class="mim-tip-reference" title="Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others. <strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong> New Eng. J. Med. 360: 1729-1739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19387015</a>] [<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19387015">Hara et al. (2009)</a> identified a homozygous 1108C-T transition in the HTRA1 gene, resulting in an arg370-to-ter (R370X) substitution. The parents were consanguineous. Studies in patient fibroblasts showed that the mutation resulted in nonsense-mediated mRNA decay and no protein production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19387015" 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> rs113993970 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993970;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/rs113993970?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=rs113993970" 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=rs113993970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), <a href="#13" class="mim-tip-reference" title="Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others. <strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong> New Eng. J. Med. 360: 1729-1739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19387015</a>] [<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19387015">Hara et al. (2009)</a> identified a homozygous 904C-T transition in the HTRA1 gene, resulting in an arg302-to-ter (R302X) substitution. Both families were consanguineous. In vitro functional expression studies showed that the R302X mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19387015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</strong>
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<p>In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), <a href="#13" class="mim-tip-reference" title="Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others. <strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong> New Eng. J. Med. 360: 1729-1739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19387015</a>] [<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19387015">Hara et al. (2009)</a> identified a homozygous 889G-A transition in the HTRA1 gene, resulting in a val297-to-met (V297M) substitution. Both families were consanguineous. In vitro functional expression studies showed that the V297M mutant had 21 to 50% normal protease activity and was unable to suppress TGF-beta activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19387015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113993968 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993968;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/rs113993968?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=rs113993968" 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=rs113993968" 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=RCV000007919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007919</a>
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<p>In 2 sibs with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), born of consanguineous Japanese parents, <a href="#13" class="mim-tip-reference" title="Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others. <strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong> New Eng. J. Med. 360: 1729-1739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19387015</a>] [<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19387015">Hara et al. (2009)</a> identified a homozygous 754G-A transition in the HTRA1 gene, resulting in an ala252-to-thr (A252T) substitution. In vitro functional expression studies showed that the A252T mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19387015" 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 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587776873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776873;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/rs587776873?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=rs587776873" 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=rs587776873" 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=RCV000023168 OR RCV001852016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023168, RCV001852016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023168...</a>
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<p>In a Caucasian man of Spanish descent with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), <a href="#17" class="mim-tip-reference" title="Mendioroz, M., Fernandez-Cadenas, I., Del Rio-Espinola, A., Rovira, A., Sole, E., Fernandez-Figueras, M. T., Garcia-Patos, V., Sastre-Garriga, J., Domingues-Montanari, S., Alvarez-Sabin, J., Montaner, J. <strong>A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population.</strong> Neurology 75: 2033-2035, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115960</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181ff96ac" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21115960">Mendioroz et al. (2010)</a> identified a homozygous 883G-A transition in exon 4 of the HTRA1 gene, resulting in a gly295-to-arg (G295R) substitution in a highly conserved residue in the binding pocket of the protease domain. Each parent was heterozygous for the mutation, which was not found in 80 controls. The patient presented at age 34 years with unsteady gait, urinary urgency, and slurred speech. He had had alopecia since before age 18 years. The disorder was progressive, and the patient subsequently developed cognitive impairment with dysexecutive syndrome, pseudobulbar syndrome, and tetraparesis. Brain MRI showed diffuse leukoencephalopathy, lacunar infarcts, and microbleeds. The patient's mother, who was heterozygous for the mutation, had nonhypertensive leukoencephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21115960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587776449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776449;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/rs587776449?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=rs587776449" 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=rs587776449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 29-year-old Romanian woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>), <a href="#3" class="mim-tip-reference" title="Bianchi, S., Di Palma, C., Gallus, G. N., Taglia, I., Poggiani, A., Rosini, F., Rufa, A., Muresanu, D. F., Cerase, A., Dotti, M. T., Federico, A. <strong>Two novel HTRA1 mutations in a European CARASIL patient.</strong> Neurology 82: 898-900, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24500651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24500651</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24500651">Bianchi et al. (2014)</a> identified compound heterozygous mutations in the HTRA1 gene: a c.961G-A transition in exon 4, resulting in an ala321-to-thr (A321T) substitution at a highly conserved residue in the serine protease domain, and a 1-bp deletion (c.126delG; <a href="#0007">602194.0007</a>) in exon 1, resulting in a frameshift (Glu42fs) and premature termination at position 214. The missense mutation was inherited from the father and the truncating mutation from the mother. The mutations, which were found by direct sequencing of the HTRA1 gene, were not present in the dbSNP (build 137) or 1000 Genomes Project databases, or in 320 control chromosomes. The father showed mild supratentorial leukoencephalopathy and the mother showed diffuse infra- and supratentorial leukoencephalopathy, but both parents were neurologically normal, suggesting that the carrier condition may be paucisymptomatic. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24500651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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">rs587776448 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776448;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=rs587776448" 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=rs587776448" 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=RCV000157766" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157766" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157766</a>
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<p>For discussion of the c.126delG mutation in the HTRA1 gene that was found in compound heterozygous state in a patient with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; <a href="/entry/600142">600142</a>) by <a href="#3" class="mim-tip-reference" title="Bianchi, S., Di Palma, C., Gallus, G. N., Taglia, I., Poggiani, A., Rosini, F., Rufa, A., Muresanu, D. F., Cerase, A., Dotti, M. T., Federico, A. <strong>Two novel HTRA1 mutations in a European CARASIL patient.</strong> Neurology 82: 898-900, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24500651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24500651</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24500651">Bianchi et al. (2014)</a>, see <a href="#0007">602194.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24500651" 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>.0009 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs864622781 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622781;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/rs864622781?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=rs864622781" 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=rs864622781" 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=RCV000206925" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000206925" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000206925</a>
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<p>By whole-exome sequencing of 3 affected individuals (2 sibs and a first cousin) in a family (F1) referred for stroke and/or cognitive impairment associated with diffuse white matter hyperintensities (CADASIL2; <a href="/entry/616779">616779</a>), <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> identified a heterozygous c.497G-T transversion (c.497G-T, NM_002775.4) in exon 2 of the HTRA1 gene, resulting in an arg166-to-leu (R166L) substitution. <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> performed a BSA assay, which showed loss of activity of the R166L mutant compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs781563777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs781563777;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/rs781563777?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=rs781563777" 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=rs781563777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> sequenced the HTRA1 gene in 201 unrelated probands with familial small vessel disease of unknown etiology and identified a c.517G-C transversion (c.517G-C, NM_002775.4) in exon 2, resulting in an ala173-to-pro (A173P) substitution, in a 72-year-old female proband (family F2) with a history of hypertension, balance impairment, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; <a href="/entry/616779">616779</a>). <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> performed a BSA assay, which showed loss of activity of the A173P mutant compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063658" 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>.0011 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</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">rs864622782 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622782;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=rs864622782" 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=rs864622782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.852C-A transversion (c.852C-A, NM_002775.4) in exon 4, resulting in a ser284-to-arg (S284R) substitution, in a 49-year-old female proband (family F3) with a history of hypertension, headache, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; <a href="/entry/616779">616779</a>). <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> performed a BSA assay, which showed partial loss of activity of the S284R mutant compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</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">rs864622783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864622783;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=rs864622783" 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=rs864622783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, <a href="#20" class="mim-tip-reference" title="Verdura, E., Herve, D., Scharrer, E., del Mar Amador, M., Guyant-Marechal, L., Philippi, A., Corlobe, A., Bergametti, F., Gazal, S., Prieto-Morin, C., Beaufort, N., Le Bail, B., Viakhireva, I., Dichgans, M., Chabriat, H., Haffner, C., Tournier-Lasserve, E. <strong>Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.</strong> Brain 138: 2347-2358, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063658</a>] [<a href="https://doi.org/10.1093/brain/awv155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063658">Verdura et al. (2015)</a> sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.973-1G-A transition (c.973-1G-A, NM_002775.4) in intron 4, resulting in a protein change of Tyr325_Leu335del, in a 66-year-old female proband (family F6) with a history of hypertension, stroke, transient ischemic attacks, confluent white matter hyperintensities, multiple lacunar infarcts, microbleeds and dilated perivascular spaces with a typical status cribrosum (CADASIL2; <a href="/entry/616779">616779</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Akhatib2013" class="mim-anchor"></a>
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Akhatib, B., Onnerfjord, P., Gawri, R., Ouellet, J., Jarzem, P., Heinegard, D., Mort, J., Roughley, P., Haglund, L.
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<strong>Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23673665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23673665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23673665[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=23673665" 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.M112.443010" target="_blank">Full Text</a>]
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Bergeron-Sawitzke, J., Gold, B., Olsh, A., Schlotterbeck, S., Lemon, K., Visvanathan, K., Allikmets, R., Dean, M.
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<strong>Multilocus analysis of age-related macular degeneration.</strong>
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Europ. J. Hum. Genet. 17: 1190-1199, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19259132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19259132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19259132[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=19259132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.23" target="_blank">Full Text</a>]
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Bianchi, S., Di Palma, C., Gallus, G. N., Taglia, I., Poggiani, A., Rosini, F., Rufa, A., Muresanu, D. F., Cerase, A., Dotti, M. T., Federico, A.
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<strong>Two novel HTRA1 mutations in a European CARASIL patient.</strong>
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Neurology 82: 898-900, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24500651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24500651</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24500651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000000202" target="_blank">Full Text</a>]
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Campbell, R. A., Campbell, H. D., Bircher, J. S., de Araujo, C. V., Denorme, F., Crandell, J. L., Rustad, J. L., Monts, J., Cody, M. J., Kosaka, Y., Yost, C. C.
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<strong>Placental HTRA1 cleaves alpha-1-antitrypsin to generate a NET-inhibitory peptide.</strong>
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Blood 138: 977-988, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34192300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34192300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34192300[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=34192300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V.
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<strong>Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.</strong>
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J. Clin. Invest. 116: 1994-2004, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16767218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16767218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[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=16767218" 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/10.1172/JCI27698" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1207271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awab271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1133807" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn167" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.170" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M500361200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0801560" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.51.34406" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0703933104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI140555" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181ff96ac" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-007-0162-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M112.341032" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17053109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1133811" 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="22" class="mim-anchor"></a>
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<a id="Zhang2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, L., Lim, S. L., Du, H., Zhang, M., Kozak, I., Hannum, G., Wang, X., Ouyang, H., Hughes, G., Zhao, L., Zhu, X., Lee, C., and 12 others.
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|
<strong>High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-beta family member growth differentiation factor 6.</strong>
|
|
J. Biol. Chem. 287: 1520-1526, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22049084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22049084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22049084[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=22049084" 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.M111.275990" 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="23" class="mim-anchor"></a>
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<a id="Zumbrunn1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zumbrunn, J., Trueb, B.
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|
<strong>Primary structure of a putative serine protease specific for IGF-binding proteins.</strong>
|
|
FEBS Lett. 398: 187-192, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8977104" 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/s0014-5793(96)01229-x" 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="24" class="mim-anchor"></a>
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<a id="Zumbrunn1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zumbrunn, J., Trueb, B.
|
|
<strong>Localization of the gene for a serine protease with IGF-binding domain (PRSS11) to human chromosome 10q25.3-q26.2.</strong>
|
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Genomics 45: 461-462, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9344681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9344681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9344681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4953" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" 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="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Hilary J. Vernon - updated : 11/14/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 08/31/2022<br>Bao Lige - updated : 08/31/2022<br>Nara Sobreira - updated : 1/29/2016<br>Cassandra L. Kniffin - updated : 2/12/2015<br>Patricia A. Hartz - updated : 4/8/2014<br>Patricia A. Hartz - updated : 11/21/2012<br>Cassandra L. Kniffin - updated : 2/15/2011<br>Marla J. F. O'Neill - updated : 8/5/2010<br>Marla J. F. O'Neill - updated : 1/27/2010<br>Cassandra L. Kniffin - updated : 4/24/2009<br>Ada Hamosh - updated : 8/6/2008<br>Carol A. Bocchini - updated : 10/16/2007<br>Cassandra L. Kniffin - updated : 7/27/2007<br>Ada Hamosh - updated : 1/10/2007<br>Marla J. F. O'Neill - updated : 11/16/2006<br>Paul J. Converse - updated : 3/27/2002
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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="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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Victor A. McKusick : 12/16/1997
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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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alopez : 05/29/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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carol : 11/18/2022<br>carol : 11/14/2022<br>carol : 11/11/2022<br>mgross : 08/31/2022<br>mgross : 08/31/2022<br>carol : 06/14/2017<br>carol : 09/21/2016<br>carol : 01/30/2016<br>carol : 1/29/2016<br>carol : 2/18/2015<br>carol : 2/18/2015<br>carol : 2/17/2015<br>mcolton : 2/16/2015<br>ckniffin : 2/12/2015<br>mgross : 4/8/2014<br>mgross : 4/8/2014<br>mcolton : 3/6/2014<br>mgross : 1/3/2013<br>mgross : 1/3/2013<br>terry : 11/21/2012<br>wwang : 3/9/2011<br>ckniffin : 2/15/2011<br>wwang : 8/5/2010<br>wwang : 1/29/2010<br>terry : 1/27/2010<br>wwang : 5/12/2009<br>ckniffin : 4/24/2009<br>ckniffin : 4/24/2009<br>carol : 2/6/2009<br>alopez : 9/8/2008<br>alopez : 9/8/2008<br>terry : 8/6/2008<br>carol : 10/16/2007<br>alopez : 10/4/2007<br>wwang : 7/31/2007<br>ckniffin : 7/27/2007<br>alopez : 1/12/2007<br>mgross : 1/12/2007<br>terry : 1/10/2007<br>wwang : 11/17/2006<br>terry : 11/16/2006<br>mgross : 3/27/2002<br>mgross : 11/6/2001<br>dholmes : 1/21/1998<br>dholmes : 1/14/1998<br>mark : 12/16/1997<br>mark : 12/16/1997
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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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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602194
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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 1; HTRA1
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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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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
HtrA, E. COLI, HOMOLOG OF; HTRA<br />
|
|
PROTEASE, SERINE, 11; PRSS11
|
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: HTRA1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 703219008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
|
<em>
|
|
Cytogenetic location: 10q26.13
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 10:122,461,553-122,514,907 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
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<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
10q26.13
|
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</span>
|
|
</td>
|
|
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|
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<td>
|
|
<span class="mim-font">
|
|
{Macular degeneration, age-related, 7}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610149
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
{Macular degeneration, age-related, neovascular type}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610149
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
CARASIL syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
600142
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616779
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
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</tbody>
|
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</table>
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</div>
|
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</div>
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<div>
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|
<br />
|
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>HTRA1 is a member of the HTRA (high temperature requirement) family of serine proteases first identified in bacteria. These proteases are characterized by a highly conserved trypsin (see 276000)-like serine protease domain and at least 1 C-terminal PDZ domain. HTRA1 also contains an insulin-like growth factor-binding protein (see 146730) domain and a Kazal-type serine protease inhibitor (see 167790) motif at its N terminus. HTRA1 can degrade several extracellular matrix components and plays a role in cancer and degenerative diseases (summary by Grau et al., 2006). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
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|
<span class="mim-text-font">
|
|
<p>Zumbrunn and Trueb (1996) cloned the cDNA for a human protein, termed L56 by them, that seemed to be part of the IGF signaling system. The predicted protein encodes a 480-amino acid polypeptide with a molecular mass of 51 kD. Zumbrunn and Trueb (1996) found that PRSS11 contains a secretory signal sequence, an IGFBP-binding domain, and a serine protease domain. The serine protease domain is most similar to certain bacterial serine proteases. By Northern blot analysis, Zumbrunn and Trueb (1996) showed that PRSS11 is expressed in a variety of human tissues, with strongest expression in placenta. </p><p>Hu et al. (1998) also cloned PRSS11. The deduced 480-amino acid protein is 98% identical to the cow, guinea pig, and rabbit proteins. It contains an N terminus homologous to MAC25 (IGFBP7; 602867) with a conserved Kazal-type serine protease inhibitor motif, as well as a C-terminal PDZ domain. Semiquantitative RT-PCR and immunoblot analyses showed an approximately 7-fold increase of PRSS11 in osteoarthritis cartilage compared with controls. Functional and mutational analyses indicated that PRS11 is a serine protease dependent on the presence of a serine at position 328. </p><p>Using in situ hybridization, Kato et al. (2021) showed that Htra1 was expressed in endothelial cells of pial arteries in mice. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Using fluorescence in situ hybridization, Zumbrunn and Trueb (1997) mapped the PRSS11 gene to chromosome 10q25.3-q26.2. </p><p>Gross (2022) mapped the HTRA1 gene to chromosome 10q26.13 based on an alignment of the HTRA1 sequence (GenBank BC011352) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chien et al. (2004) found that HTRA1 was downregulated in 59% of primary ovarian tumors and observed high frequencies for LOH at microsatellite markers near HTRA1 on 10q26. Antisense transfection studies showed that downregulation of HTRA1 promoted anchorage-independent growth, while exogenous expression induced cell death. Chien et al. (2004) suggested that HTRA1 may be a tumor suppressor involved in promoting serine-protease-mediated cell death. </p><p>Chien et al. (2006) demonstrated that downregulation of HTRA1 in ovarian cancer cell lines attenuated cisplatin- and paclitaxel-induced cytotoxicity, whereas forced expression of HTRA1 enhanced chemotherapeutic cytotoxicity. Patients with ovarian epithelial (167000) or gastric (137215) tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. </p><p>Using ELISA, Grau et al. (2006) found that expression of HTRA1 was upregulated in synovial fluid from both osteoarthritis (OA; see 165720) and rheumatoid arthritis (RA; see 180300) patients compared with normal human fluid. HTRA1 was also highly expressed in and secreted by cultured OA and RA synovial fibroblasts, but not by normal human foreskin fibroblasts. Recombinant human HTRA1 lacking the N-terminal IGF-binding and serine protease inhibitor domains, representing an autoproteolytically processed form, degraded purified human fibronectin (FN1; 135600) into several fragments. Synovial fibroblasts exposed to these fragments subsequently upregulated mRNA expression and secretion of the matrix metalloproteases MMP1 (120353) and MMP3 (185250). Inhibition of HTRA1 abrogated fibronectin fragment formation and MMP upregulation. Grau et al. (2006) concluded that HTRA1 can contribute to destruction of extracellular matrix through both direct and indirect mechanisms. </p><p>Using quantitative RT-PCR analysis, Tiaden et al. (2012) found that expression of HTRA1 was upregulated in degenerating patient intervertebral discs (IVDs), and expression of HTRA1 positively correlated with disease severity. Western blot analysis detected both full-length and processed HTRA1 species at apparent molecular masses of 50 and 42 kD, respectively. The 42-kD form was found in patient IVD samples only, and the amount increased with severity of disease. Cultured IVD fibroblasts exposed to recombinant HTRA1 lacking the N-terminal domains responded by increasing their expression of MMP1 and MMP3, as well as a specific subset of other matrix proteases. IVD cells exposed to HTRA1-generated fibronectin fragments also showed upregulation and activation of MMPs. This effect was not observed in cells exposed to inactivated truncated HTRA1 or following HTRA1 inhibition. </p><p>Akhatib et al. (2013) found that chondroadherin (CHAD; 602178) was intact in normal human IVDs, but that it was fragmented in adults with IVD degeneration and in damaged discs in adolescent idiopathic scoliosis. The amount of fragmented CHAD correlated with severity of disease, but in all cases, CHAD was specifically cleaved between ile80 and tyr81. Akhatib et al. (2013) found that the CHAD cleavage site generated by HTRA1 was identical to that present in situ. HTRA1 protein was observed in both degenerate adult and adolescent scoliotic samples and was elevated compared with normal disc samples. Akhatib et al. (2013) concluded that HTRA1 plays a role in CHAD fragmentation in degenerating disc diseases. </p><p>Neonatal neutrophils fail to form neutrophil extracellular traps (NETs) due to circulating NET inhibitory peptides (NIPs), which are cleavage fragments of alpha-1-antitrypsin (A1AT, or SERPINA1; 107400). Using immunofluorescence assays, Campbell et al. (2021) showed that human placenta from both term and preterm pregnancies secreted HTRA1 into fetal circulation. Plasma HTRA1 levels were reduced after delivery, and decreased HTRA1 plasma levels were associated with decreased levels of NIPs. Placental HTRA1 cleaved A1AT after amino acid 382 to generate a C-terminal cleavage fragment of A1AT, termed A1ATM383S-CF, that could inhibit NET formation in vitro. Through NET inhibition, A1ATM383S-CF decreased bacterial killing, but it maintained other key neutrophil activities in vitro. In vivo analysis with wildtype mice showed that mouse placenta also secreted Htra1, and placental Htra1 cleaved A1at to generate A1atM383S-CF and inhibit NET formation by neonatal neutrophils. Analysis with Htra1 -/- and wildtype mice revealed that inhibition of NET formation during experimental neonatal sepsis improved survival. </p>
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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>Age-Related Macular Degeneration 7</em></strong></p><p>
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From a cohort of Southeast Asians in Hong Kong, DeWan et al. (2006) identified 96 patients who had been previously diagnosed with wet age-related macular degeneration (ARMD7; 610149) and 138 matched control individuals who were ARMD-free. Because the putative locus on 10q26 in which a previously identified SNP with significant association with ARMD had been removed from GenBank (see LOC387715, 611313), DeWan et al. (2006) sequenced the entire local genomic region, including promoters, exons, and intron-exon junctions of PLEKHA1 (607772) and HTRA1, in search of the functional variant. They found that 1 SNP in the promoter region of HTRA1, rs11200638 (602194.0001), located 512 base pairs upstream of the HTRA1 putative transcriptional start site and 6,096 basepairs downstream of the previously identified SNP, exhibited a complete linkage disequilibrium pattern with the previously identified SNP. The SNP rs11200638 resides within putative binding sites for the transcription factors adaptor-related protein complex 2-alpha (AP2-alpha; 107580) and serum response factor (SRF; 600589). Preliminary results showed higher HTRA1 expression correlated with the risk (AA) compared with the wildtype (GG) genotype in in vitro transfection assays. </p><p>Yang et al. (2006) independently identified the same SNP in the HTRA1 promoter region as causative of age-related macular degeneration in a Caucasian cohort in Utah. The authors suggested that the estimated population-attributable risk for the SNP is 49.3%. Consistent with an additive effect, the estimated population-attributable risk from a joint model with CFH Y402H (134370.0008) (i.e., for a risk allele at either locus) is 71.4%. </p><p>Contrary to the findings of DeWan et al. (2006) and Yang et al. (2006), Kanda et al. (2007) found that rs11200638 had no significant impact on HTRA1 promoter activity in 3 different cells lines, and that HTRA1 mRNA expression exhibited no significant change between control and ARMD retinas. By evaluating 45 tag SNPs spanning the HTRA1, PLEKHA1, and LOC387715 in 466 cases of ARMD and 280 controls, they determined that rs10490924 in the LOC387715 gene alone, or a variant in strong linkage disequilibrium, could explain the bulk of the association between the 10q26 region and ARMD, whereas rs11200638 in the HTRA1 gene could not. They concluded that the association of the HTRA1 polymorphism with ARMD susceptibility was likely to be indirect. </p><p>In a resequencing study of the locus on chromosome 10q26 associated with ARMD, Fritsche et al. (2008) identified an insertion/deletion polymorphism in the LOC387715 gene (611313.0002) that was highly associated with ARMD and that generated an unstable mRNA. The authors also confirmed association of the SNP rs11200638 and identified an intronic SNP that they considered 'unlikely to exert consequences on gene function.' </p><p><strong><em>Autosomal Recessive Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy</em></strong></p><p>
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Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142) is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. By linkage analysis and fine mapping, followed by candidate gene sequencing, in 6 consanguineous Japanese families with CARASIL, Hara et al. (2009) identified 4 different homozygous mutations in the HTRA1 gene (602194.0002-602194.0005). The mutant proteins were unable to repress TGF-beta (190180) activity, and increased expression TGFB1 was observed in the tunica media of affected small arteries. These findings indicated that CARASIL is a disease associated with dysregulation of TGF-beta signaling. </p><p><strong><em>Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Type 2</em></strong></p><p>
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Using whole-exome sequencing to identify candidate genes in a family with autosomal dominant small vessel disease (cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2; CADASIL2; 616779) in which known small vessel disease genes had been excluded, Verdura et al. (2015) identified heterozygosity for a missense mutation (R166L; 602194.0001) in the HTRA1 gene in all affected members. The mutation was not present in the 1000 Genomes Project and the EVS databases. The authors subsequently used high-throughput multiplex polymerase chain reaction and next-generation sequencing to screen all candidate genes in 201 unrelated probands from families with small vessel disease of unknown etiology. Ten of the probands (4.97%) harbored a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (p = 4.2 x 10(-6); odds ratio = 15.4; 95% CI = 4.9 - 45.5), strongly suggesting causality. In vitro activity analysis of HTRA1 mutants demonstrated a loss-of-function effect. </p><p>In a cohort of 3,853 unrelated patients with cerebral small vessel disease, Coste et al. (2021) identified 20 patients with heterozygous mutations in the HTRA1 gene leading to a premature stop codon, including 8 nonsense, 7 frameshift, and 2 canonical splice site mutations. This represented a highly significant enrichment of stop codon mutations in the HTRA1 gene compared to what was reported in control population databases, including the 1000 Genomes Project (in which no stop mutations were reported), gnomAD (v.3.1.1), and TOPmed (freeze 5) databases. RNA was available for 8 of the patients, and RT-PCR followed by Sanger sequencing analysis was consistent with nonsense-mediated decay of the mutant allele. Coste et al. (2021) concluded that heterozygous mutations in the HTRA1 gene leading to a premature stop are a cause of CADASIL2. Clinical features of the patients with nonsense mutations in the HTRA1 gene were not different from other patients with CADASIL2, other than a likely lower penetrance, as only 61% of the patients had an affected relative. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Francis et al. (2008) genotyped 137 unrelated rhesus macaques, 81 with and 56 without macular drusen, and identified a variant in the Htra1 gene that was significantly associated with affected status. Functional analysis of the polymorphic variant showed a 2-fold increase in gene expression, supporting a role in pathogenesis. Francis et al. (2008) stated that this was the first evidence that humans and macaques share the same genetic susceptibility factors for common complex disease. </p><p>Zhang et al. (2012) found that Htra1 -/- mice showed reduced retinal vasculature compared with wildtype. Knockout of Htra1 significantly upregulated expression of Gdf6 (601147) and downregulated expression of Vegf (192240) in retinal pigment epithelia. Increased levels of phosphorylated Smad1 (601595), Smad5 (603110), and Smad8 (SMAD9; 603295), which are downstream effectors of Gdf6 signaling, were present in Htra1 -/- brain. Zhang et al. (2012) concluded that HTRA1 regulates angiogenesis via TGF-beta signaling by GDF6. </p><p>Kato et al. (2021) found that Htra1 -/- mice had normal blood pressure, blood glucose levels, and vascular density in brain parenchyma, with no motor deficits, white matter lesions, or ischemic lesions. However, Htra1 -/- mice exhibited accumulation of matrisome proteins, which are components of the extracellular matrix, in pial arteries and arterioles, recapitulating features of patients with CARASIL. Administration of candesartan, an angiotensin II type-1 receptor (AGTR1; 106165) inhibitor, ameliorated accumulation of matrisome proteins and prevented vascular remodeling and decreased cerebral blood flow in Htra1 -/- mice, but it failed to prevent alterations in smooth muscle cells and pericytes. Furthermore, RNA-sequencing analysis showed that candesartan reduced expression of Fn1 (135600), Ltbp4 (604710), and Adamtsl2 (612277), which are involved in forming the extracellular matrix network. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 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 MACULAR DEGENERATION, AGE-RELATED, 7, 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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MACULAR DEGENERATION, AGE-RELATED, NEOVASCULAR TYPE, SUSCEPTIBILITY TO, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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HTRA1, -512G-A ({dbSNP rs11200638})
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<br />
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SNP: rs11200638,
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gnomAD: rs11200638,
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ClinVar: RCV000007914, RCV000007915
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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>DeWan et al. (2006) identified a SNP (rs11200638) for which homozygosity for the AA genotype results in a 10-fold (confidence intervals 4.38 to 22.82) increased risk of wet age-related macular degeneration (see ARMD7, 610149) in a Southeast Asian population identified in Hong Kong. Yang et al. (2006) independently identified this variant as conferring risk in a Caucasian cohort from Utah. </p><p>Mori et al. (2007) found a significant association between the -512A allele and ARMD among 123 Japanese patients and 133 Japanese controls. The frequency of the risk A allele was 0.577 and 0.380 in patients and controls, respectively, yielding an odds ratio of 2.23 (p = 7.75 x 10(-6)). The results were more significant in a subset of 104 Japanese patients with wet ARMD (p = 5.96 x 10(-7)). The association was significant in both nonsmokers and smokers, and was more significant in nonsmokers. </p><p>Fritsche et al. (2008) identified rs11200638 as 1 of 6 highly correlated risk alleles residing on a single risk haplotype within the 23.3-kb region on chromosome 10q26 associated with age-related macular degeneration (P = 6.9 x 10(-29)). </p><p>In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and rs11200638, with both the GA (OR, 3.2; p = 8.7 x 10(-9)) and AA (OR, 9.1; p = 6.4 x 10(-10)) genotypes. Bergeron-Sawitzke et al. (2009) noted that rs11200638 is in strong linkage disequilibrium with the rs10490924 SNP (611313.0001) in the LOC387715 gene that has also been associated with ARMD. </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 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, ARG370TER
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<br />
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SNP: rs113993971,
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gnomAD: rs113993971,
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ClinVar: RCV000007916, RCV000779017, RCV002512882
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 1108C-T transition in the HTRA1 gene, resulting in an arg370-to-ter (R370X) substitution. The parents were consanguineous. Studies in patient fibroblasts showed that the mutation resulted in nonsense-mediated mRNA decay and no protein production. </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 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, ARG302TER
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<br />
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SNP: rs113993970,
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gnomAD: rs113993970,
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ClinVar: RCV000007917, RCV001003543, RCV001003928, RCV001250521, RCV001851726
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 904C-T transition in the HTRA1 gene, resulting in an arg302-to-ter (R302X) substitution. Both families were consanguineous. In vitro functional expression studies showed that the R302X mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, VAL297MET
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<br />
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SNP: rs113993969,
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ClinVar: RCV000007918
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 889G-A transition in the HTRA1 gene, resulting in a val297-to-met (V297M) substitution. Both families were consanguineous. In vitro functional expression studies showed that the V297M mutant had 21 to 50% normal protease activity and was unable to suppress TGF-beta activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, ALA252THR
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<br />
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SNP: rs113993968,
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gnomAD: rs113993968,
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ClinVar: RCV000007919
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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 with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), born of consanguineous Japanese parents, Hara et al. (2009) identified a homozygous 754G-A transition in the HTRA1 gene, resulting in an ala252-to-thr (A252T) substitution. In vitro functional expression studies showed that the A252T mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, GLY295ARG
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<br />
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SNP: rs587776873,
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gnomAD: rs587776873,
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ClinVar: RCV000023168, RCV001852016
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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 Caucasian man of Spanish descent with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Mendioroz et al. (2010) identified a homozygous 883G-A transition in exon 4 of the HTRA1 gene, resulting in a gly295-to-arg (G295R) substitution in a highly conserved residue in the binding pocket of the protease domain. Each parent was heterozygous for the mutation, which was not found in 80 controls. The patient presented at age 34 years with unsteady gait, urinary urgency, and slurred speech. He had had alopecia since before age 18 years. The disorder was progressive, and the patient subsequently developed cognitive impairment with dysexecutive syndrome, pseudobulbar syndrome, and tetraparesis. Brain MRI showed diffuse leukoencephalopathy, lacunar infarcts, and microbleeds. The patient's mother, who was heterozygous for the mutation, had nonhypertensive leukoencephalopathy. </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 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, ALA321THR
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<br />
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SNP: rs587776449,
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gnomAD: rs587776449,
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ClinVar: RCV000144150, RCV000157765, RCV001263182, RCV001797058
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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 29-year-old Romanian woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Bianchi et al. (2014) identified compound heterozygous mutations in the HTRA1 gene: a c.961G-A transition in exon 4, resulting in an ala321-to-thr (A321T) substitution at a highly conserved residue in the serine protease domain, and a 1-bp deletion (c.126delG; 602194.0007) in exon 1, resulting in a frameshift (Glu42fs) and premature termination at position 214. The missense mutation was inherited from the father and the truncating mutation from the mother. The mutations, which were found by direct sequencing of the HTRA1 gene, were not present in the dbSNP (build 137) or 1000 Genomes Project databases, or in 320 control chromosomes. The father showed mild supratentorial leukoencephalopathy and the mother showed diffuse infra- and supratentorial leukoencephalopathy, but both parents were neurologically normal, suggesting that the carrier condition may be paucisymptomatic. Functional studies of the variants were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY</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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HTRA1, 1-BP DEL, 126G
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<br />
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SNP: rs587776448,
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ClinVar: RCV000157766
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.126delG mutation in the HTRA1 gene that was found in compound heterozygous state in a patient with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142) by Bianchi et al. (2014), see 602194.0007. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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HTRA1, ARG166LEU
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<br />
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SNP: rs864622781,
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gnomAD: rs864622781,
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|
ClinVar: RCV000206925
|
|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>By whole-exome sequencing of 3 affected individuals (2 sibs and a first cousin) in a family (F1) referred for stroke and/or cognitive impairment associated with diffuse white matter hyperintensities (CADASIL2; 616779), Verdura et al. (2015) identified a heterozygous c.497G-T transversion (c.497G-T, NM_002775.4) in exon 2 of the HTRA1 gene, resulting in an arg166-to-leu (R166L) substitution. Verdura et al. (2015) performed a BSA assay, which showed loss of activity of the R166L mutant compared to controls. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
|
|
</span>
|
|
</h4>
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|
</div>
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<div>
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<span class="mim-text-font">
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HTRA1, ALA173PRO
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<br />
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SNP: rs781563777,
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gnomAD: rs781563777,
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ClinVar: RCV000206984
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with familial small vessel disease of unknown etiology and identified a c.517G-C transversion (c.517G-C, NM_002775.4) in exon 2, resulting in an ala173-to-pro (A173P) substitution, in a 72-year-old female proband (family F2) with a history of hypertension, balance impairment, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779). Verdura et al. (2015) performed a BSA assay, which showed loss of activity of the A173P mutant compared to controls. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
HTRA1, SER284ARG
|
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|
|
<br />
|
|
|
|
SNP: rs864622782,
|
|
|
|
|
|
|
|
ClinVar: RCV000206899
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.852C-A transversion (c.852C-A, NM_002775.4) in exon 4, resulting in a ser284-to-arg (S284R) substitution, in a 49-year-old female proband (family F3) with a history of hypertension, headache, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779). Verdura et al. (2015) performed a BSA assay, which showed partial loss of activity of the S284R mutant compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HTRA1, IVS4AS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864622783,
|
|
|
|
|
|
|
|
ClinVar: RCV000206946
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.973-1G-A transition (c.973-1G-A, NM_002775.4) in intron 4, resulting in a protein change of Tyr325_Leu335del, in a 66-year-old female proband (family F6) with a history of hypertension, stroke, transient ischemic attacks, confluent white matter hyperintensities, multiple lacunar infarcts, microbleeds and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Akhatib, B., Onnerfjord, P., Gawri, R., Ouellet, J., Jarzem, P., Heinegard, D., Mort, J., Roughley, P., Haglund, L.
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<strong>Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging.</strong>
|
|
J. Biol. Chem. 288: 19280-19287, 2013.
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[PubMed: 23673665]
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[Full Text: https://doi.org/10.1074/jbc.M112.443010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bergeron-Sawitzke, J., Gold, B., Olsh, A., Schlotterbeck, S., Lemon, K., Visvanathan, K., Allikmets, R., Dean, M.
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<strong>Multilocus analysis of age-related macular degeneration.</strong>
|
|
Europ. J. Hum. Genet. 17: 1190-1199, 2009.
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[PubMed: 19259132]
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[Full Text: https://doi.org/10.1038/ejhg.2009.23]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bianchi, S., Di Palma, C., Gallus, G. N., Taglia, I., Poggiani, A., Rosini, F., Rufa, A., Muresanu, D. F., Cerase, A., Dotti, M. T., Federico, A.
|
|
<strong>Two novel HTRA1 mutations in a European CARASIL patient.</strong>
|
|
Neurology 82: 898-900, 2014.
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[PubMed: 24500651]
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[Full Text: https://doi.org/10.1212/WNL.0000000000000202]
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<li>
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<p class="mim-text-font">
|
|
Campbell, R. A., Campbell, H. D., Bircher, J. S., de Araujo, C. V., Denorme, F., Crandell, J. L., Rustad, J. L., Monts, J., Cody, M. J., Kosaka, Y., Yost, C. C.
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|
<strong>Placental HTRA1 cleaves alpha-1-antitrypsin to generate a NET-inhibitory peptide.</strong>
|
|
Blood 138: 977-988, 2021.
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[PubMed: 34192300]
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[Full Text: https://doi.org/10.1182/blood.2020009021]
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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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Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V.
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<strong>Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.</strong>
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|
J. Clin. Invest. 116: 1994-2004, 2006.
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[PubMed: 16767218]
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[Full Text: https://doi.org/10.1172/JCI27698]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chien, J., Staub, J., Hu, S.-I., Erickson-Johnson, M. R., Couch, F. J., Smith, D. I., Crowl, R. M., Kaufmann, S. H., Shridhar, V.
|
|
<strong>A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer.</strong>
|
|
Oncogene 23: 1636-1644, 2004.
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|
|
[PubMed: 14716297]
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[Full Text: https://doi.org/10.1038/sj.onc.1207271]
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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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Coste, T., Herve, D., Neau, J. P., Jouvent, E., Ba, F., Bergametti, F., Lamy, M., Cogez, J., Derache, N., Schneckenburger, R., Grelet, M., Gollion, C., and 12 others.
|
|
<strong>Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.</strong>
|
|
Brain 144: 2616-2624, 2021.
|
|
|
|
|
|
[PubMed: 34270682]
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|
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|
[Full Text: https://doi.org/10.1093/brain/awab271]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
DeWan, A., Liu, M., Hartman, S., Zhang, S. S.-M., Liu, D. T. L., Zhao, C., Tam, P. O. S., Chan, W. M., Lam, D. S. C., Snyder, M., Barnstable, C., Pang, C. P., Hoh, J.
|
|
<strong>HTRA1 promoter polymorphism in wet age-related macular degeneration.</strong>
|
|
Science 314: 989-992, 2006.
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|
|
[PubMed: 17053108]
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|
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|
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[Full Text: https://doi.org/10.1126/science.1133807]
|
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Francis, P. J., Appukuttan, B., Simmons, E., Landauer, N., Stoddard, J., Hamon, S., Ott, J., Ferguson, B., Klein, M., Stout, J. T., Neuringer, M.
|
|
<strong>Rhesus monkeys and humans share common susceptibility genes for age-related macular diseases.</strong>
|
|
Hum. Molec. Genet. 17: 2673-2680, 2008.
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|
|
[PubMed: 18535016]
|
|
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|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn167]
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|
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Fritsche, L. G., Loenhardt, T., Janssen, A., Fisher, S. A., Rivera, A., Keilhauer, C. N., Weber, B. H. F.
|
|
<strong>Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA.</strong>
|
|
Nature Genet. 40: 892-896, 2008.
|
|
|
|
|
|
[PubMed: 18511946]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.170]
|
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Grau, S., Richards, P. J., Kerr, B., Hughes, C., Caterson, B., Williams, A. S., Junker, U., Jones, S. A., Clausen, T., Ehrmann, M.
|
|
<strong>The role of human HtrA1 in arthritic disease.</strong>
|
|
J. Biol. Chem. 281: 6124-6129, 2006.
|
|
|
|
|
|
[PubMed: 16377621]
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|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M500361200]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gross, M. B.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 8/31/2022.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A., Kawata, H., Koyama, A., Arima, K., Takahashi, T., Ikeda, M., Shiota, H., and 15 others.
|
|
<strong>Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.</strong>
|
|
New Eng. J. Med. 360: 1729-1739, 2009.
|
|
|
|
|
|
[PubMed: 19387015]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJMoa0801560]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hu, S.-I., Carozza, M., Klein, M., Nantermet, P., Luk, D., Crowl, R. M.
|
|
<strong>Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage.</strong>
|
|
J. Biol. Chem. 273: 34406-34412, 1998.
|
|
|
|
|
|
[PubMed: 9852107]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.273.51.34406]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Kanda, A., Chen, W., Othman, M., Branham, K. E. H., Brooks, M., Khanna, R., He, S., Lyons, R., Abecasis, G. R., Swaroop, A.
|
|
<strong>A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 16227-16232, 2007.
|
|
|
|
|
|
[PubMed: 17884985]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0703933104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kato, T., Manabe, R. I., Igarashi, H., Kametani, F., Hirokawa, S., Sekine, Y., Fujita, N., Saito, S., Kawashima, Y., Hatano, Y., Ando, S., Nozaki, H., and 18 others.
|
|
<strong>Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.</strong>
|
|
J. Clin. Invest. 131: e140555, 2021.
|
|
|
|
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