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<title>
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Entry
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- #614519 - HEMORRHAGE, INTRACEREBRAL, SUSCEPTIBILITY TO; ICH
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- OMIM
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<p>
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<span class="h4">#614519</span>
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<br />
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<strong>Table of Contents</strong>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-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=" 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 in 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://clinicaltrials.gov/search?cond=(HEMORRHAGE, INTRACEREBRAL) OR (COL4A1 OR COL4A2 OR ACE)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8504" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ace" 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=614519[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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<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 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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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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614519
|
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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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HEMORRHAGE, INTRACEREBRAL, SUSCEPTIBILITY TO; ICH
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
STROKE, HEMORRHAGIC, SUSCEPTIBILITY TO
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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="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
|
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Phenotype
|
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</th>
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
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</th>
|
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<th>
|
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Gene/Locus <br /> MIM number
|
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</th>
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</tr>
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</thead>
|
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<tbody>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/geneMap/13/311?start=-3&limit=10&highlight=311">
|
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13q34
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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{Hemorrhage, intracerebral, susceptibility to}
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614519"> 614519 </a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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COL4A1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/120130"> 120130 </a>
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/13/312?start=-3&limit=10&highlight=312">
|
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13q34
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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{Hemorrhage, intracerebral, susceptibility to}
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614519"> 614519 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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COL4A2
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/120090"> 120090 </a>
|
|
</span>
|
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</td>
|
|
</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/834?start=-3&limit=10&highlight=834">
|
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17q23.3
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>A number sign (#) is used with this entry because susceptibility to intracerebral hemorrhage (ICH) can be conferred by heterozygous mutation in the COL4A2 (<a href="/entry/120090">120090</a>) or COL4A1 (<a href="/entry/120130">120130</a>) genes, both on chromosome 13q34, or by variation in the ACE gene (<a href="/entry/106180">106180</a>) on chromosome 17q23.</p><p>See also ischemic stroke (<a href="/entry/601367">601367</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J., Valant, V., Greenberg, S. M., Rosand, J., Gould, D. B. <strong>COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.</strong> Am. J. Hum. Genet. 90: 91-101, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209247[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/10.1016/j.ajhg.2011.11.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209247">Jeanne et al. (2012)</a> reported 4 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A2 gene (<a href="/entry/120090#0003">120090.0003</a>-<a href="/entry/120090#0005">120090.0005</a>). One patient was a 72-year-old white man with probable CAA (<a href="/entry/605714">605714</a>)-related ICH in the right occipital lobe. He had no family history of ICH, and was not taking aspirin or an anticoagulant at the time of his hemorrhage. The second was a 72-year-old white woman with a history of hypertension who developed hemorrhage in the left basal ganglia while taking aspirin. There was no family history of ICH. The third affected individual was a 45-year-old Hispanic man with a history of hypertension who developed hemorrhage in the left basal ganglia. He was not taking aspirin or anticoagulant at the time of his hemorrhage. Two sisters of this patient had ICH, although they were not available for study. The last patient was a 69-year-old African American man with probable CAA-related ICH in the right occipital lobe. He was not taking aspirin or anticoagulant at the time of his hemorrhage, and had no family history of ICH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22209247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Weng, Y.-C., Sonni, A., Labelle-Dumais, C., de Leau, M., Kauffman, W. B., Jeanne, M., Biffi, A., Greenberg, S. M., Rosand, J., Gould, D. B. <strong>COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.</strong> Ann. Neurol. 71: 470-477, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22522439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22522439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22522439[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.22682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22522439">Weng et al. (2012)</a> reported 2 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A1 gene (<a href="/entry/120130#0015">120130.0015</a> and <a href="/entry/120130#0016">120130.0016</a>). One was a 73-year-old Hispanic woman who presented with a generalized tonic-clonic seizure followed by left-sided weakness in the setting of oral warfarin anticoagulation therapy for aortic valve replacement. CT showed a small right temporal ICH and MRI identified lobar microbleeds, consistent with a diagnosis of probable CAA. The second patient was a 55-year-old man of European-American ancestry who presented with a large right putamen ICH causing acute-onset left arm, face, and leg weakness, and depressed consciousness. Medical history was significant for hypertension, type 2 diabetes and low-dose aspirin use. The scenario was consistent with a diagnosis of probable hypertensive hemorrhage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22522439" 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>Association with the ACE Gene</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Slowik, A., Turaj, W., Dziedzic, T., Haefele, A., Pera, J., Malecki, M. T., Glodzik-Sobanska, L., Szermer, P., Figlewicz, D. A., Szczudlik, A. <strong>DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.</strong> Neurology 63: 359-361, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277638</a>] [<a href="https://doi.org/10.1212/01.wnl.0000130200.12993.0c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277638">Slowik et al. (2004)</a> found an association between the ACE DD genotype (<a href="/entry/106180#0001">106180.0001</a>) and spontaneous intracerebral hemorrhagic stroke in deep brain structures in 58 Polish patients (OR of 2.46). No association was found between the DD genotype and 140 controls or 70 Polish patients with small vessel disease and ischemic stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15277638" 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>Association with the COL4A2 Gene</em></strong></p><p>
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In 4 of 96 unrelated patients with adult-onset intracerebral hemorrhage, <a href="#1" class="mim-tip-reference" title="Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J., Valant, V., Greenberg, S. M., Rosand, J., Gould, D. B. <strong>COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.</strong> Am. J. Hum. Genet. 90: 91-101, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209247[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/10.1016/j.ajhg.2011.11.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209247">Jeanne et al. (2012)</a> identified 3 different pathogenic mutations in the COL4A2 gene (<a href="/entry/120090#0003">120090.0003</a>-<a href="/entry/120090#0005">120090.0005</a>). COL4A2 was selected as a candidate for sequencing because COL4A1 (<a href="/entry/120130">120130</a>), with which it forms a heterotrimer, can cause cerebrovascular disease (POREN1, <a href="/entry/175780">175780</a> and HANAC, <a href="/entry/611773">611773</a>). In vitro functional expression studies showed that the COL4A2 mutations resulted in significantly decreased extracellular-to-intracellular ratios of COL4A2 and COL4A1, indicating interference with the proper secretion of both of these proteins. Intracellular immunolabeling demonstrated that the reduction in extracellular-to-intracellular COL4A1 and COL4A2 ratios resulted from retention within the endoplasmic reticulum (ER). All patients developed hemorrhagic stroke as adults, and 2 had no family history of the disorder. <a href="#1" class="mim-tip-reference" title="Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J., Valant, V., Greenberg, S. M., Rosand, J., Gould, D. B. <strong>COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.</strong> Am. J. Hum. Genet. 90: 91-101, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209247[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/10.1016/j.ajhg.2011.11.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209247">Jeanne et al. (2012)</a> noted that none of the putative mutations were glycine missense variants, which, in COL4A1, are well established to underlie severe, early-onset, and highly penetrant cerebrovascular diseases. Thus, nonglycine variants may represent alleles that result in milder disease later in life or become pathogenic as a consequence of interactions with other factors that predispose to ICH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22209247" 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>Association with the COL4A1 Gene</em></strong></p><p>
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In 2 of 96 patients with adult-onset hemorrhagic stroke, <a href="#3" class="mim-tip-reference" title="Weng, Y.-C., Sonni, A., Labelle-Dumais, C., de Leau, M., Kauffman, W. B., Jeanne, M., Biffi, A., Greenberg, S. M., Rosand, J., Gould, D. B. <strong>COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.</strong> Ann. Neurol. 71: 470-477, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22522439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22522439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22522439[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.22682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22522439">Weng et al. (2012)</a> identified different heterozygous mutations in the COL4A1 gene (<a href="/entry/120130#0015">120130.0015</a> and <a href="/entry/120130#0016">120130.0016</a>). The COL4A1 gene was chosen for study because mutation in this gene can cause rare familial forms of cerebrovascular disease. In vitro cellular studies showed that both mutant proteins were retained intracellularly and impaired normal COL4A1 secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22522439" 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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Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J., Valant, V., Greenberg, S. M., Rosand, J., Gould, D. B.
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<strong>COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.</strong>
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Am. J. Hum. Genet. 90: 91-101, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209247[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=22209247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Slowik, A., Turaj, W., Dziedzic, T., Haefele, A., Pera, J., Malecki, M. T., Glodzik-Sobanska, L., Szermer, P., Figlewicz, D. A., Szczudlik, A.
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Neurology 63: 359-361, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277638</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15277638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000130200.12993.0c" target="_blank">Full Text</a>]
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Weng, Y.-C., Sonni, A., Labelle-Dumais, C., de Leau, M., Kauffman, W. B., Jeanne, M., Biffi, A., Greenberg, S. M., Rosand, J., Gould, D. B.
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<strong>COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.</strong>
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Ann. Neurol. 71: 470-477, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22522439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22522439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22522439[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=22522439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.22682" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/18/2012
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Cassandra L. Kniffin : 3/5/2012
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joanna : 06/29/2016
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carol : 12/19/2012<br>ckniffin : 12/18/2012<br>carol : 3/7/2012<br>terry : 3/5/2012<br>ckniffin : 3/5/2012
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<strong>#</strong> 614519
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HEMORRHAGE, INTRACEREBRAL, SUSCEPTIBILITY TO; ICH
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STROKE, HEMORRHAGIC, SUSCEPTIBILITY TO
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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13q34
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{Hemorrhage, intracerebral, susceptibility to}
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614519
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3
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COL4A1
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120130
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13q34
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{Hemorrhage, intracerebral, susceptibility to}
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614519
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COL4A2
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120090
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17q23.3
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{Stroke, hemorrhagic}
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614519
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3
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ACE
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106180
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to intracerebral hemorrhage (ICH) can be conferred by heterozygous mutation in the COL4A2 (120090) or COL4A1 (120130) genes, both on chromosome 13q34, or by variation in the ACE gene (106180) on chromosome 17q23.</p><p>See also ischemic stroke (601367).</p>
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<strong>Clinical Features</strong>
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<p>Jeanne et al. (2012) reported 4 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A2 gene (120090.0003-120090.0005). One patient was a 72-year-old white man with probable CAA (605714)-related ICH in the right occipital lobe. He had no family history of ICH, and was not taking aspirin or an anticoagulant at the time of his hemorrhage. The second was a 72-year-old white woman with a history of hypertension who developed hemorrhage in the left basal ganglia while taking aspirin. There was no family history of ICH. The third affected individual was a 45-year-old Hispanic man with a history of hypertension who developed hemorrhage in the left basal ganglia. He was not taking aspirin or anticoagulant at the time of his hemorrhage. Two sisters of this patient had ICH, although they were not available for study. The last patient was a 69-year-old African American man with probable CAA-related ICH in the right occipital lobe. He was not taking aspirin or anticoagulant at the time of his hemorrhage, and had no family history of ICH. </p><p>Weng et al. (2012) reported 2 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A1 gene (120130.0015 and 120130.0016). One was a 73-year-old Hispanic woman who presented with a generalized tonic-clonic seizure followed by left-sided weakness in the setting of oral warfarin anticoagulation therapy for aortic valve replacement. CT showed a small right temporal ICH and MRI identified lobar microbleeds, consistent with a diagnosis of probable CAA. The second patient was a 55-year-old man of European-American ancestry who presented with a large right putamen ICH causing acute-onset left arm, face, and leg weakness, and depressed consciousness. Medical history was significant for hypertension, type 2 diabetes and low-dose aspirin use. The scenario was consistent with a diagnosis of probable hypertensive hemorrhage. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Association with the ACE Gene</em></strong></p><p>
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Slowik et al. (2004) found an association between the ACE DD genotype (106180.0001) and spontaneous intracerebral hemorrhagic stroke in deep brain structures in 58 Polish patients (OR of 2.46). No association was found between the DD genotype and 140 controls or 70 Polish patients with small vessel disease and ischemic stroke. </p><p><strong><em>Association with the COL4A2 Gene</em></strong></p><p>
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In 4 of 96 unrelated patients with adult-onset intracerebral hemorrhage, Jeanne et al. (2012) identified 3 different pathogenic mutations in the COL4A2 gene (120090.0003-120090.0005). COL4A2 was selected as a candidate for sequencing because COL4A1 (120130), with which it forms a heterotrimer, can cause cerebrovascular disease (POREN1, 175780 and HANAC, 611773). In vitro functional expression studies showed that the COL4A2 mutations resulted in significantly decreased extracellular-to-intracellular ratios of COL4A2 and COL4A1, indicating interference with the proper secretion of both of these proteins. Intracellular immunolabeling demonstrated that the reduction in extracellular-to-intracellular COL4A1 and COL4A2 ratios resulted from retention within the endoplasmic reticulum (ER). All patients developed hemorrhagic stroke as adults, and 2 had no family history of the disorder. Jeanne et al. (2012) noted that none of the putative mutations were glycine missense variants, which, in COL4A1, are well established to underlie severe, early-onset, and highly penetrant cerebrovascular diseases. Thus, nonglycine variants may represent alleles that result in milder disease later in life or become pathogenic as a consequence of interactions with other factors that predispose to ICH. </p><p><strong><em>Association with the COL4A1 Gene</em></strong></p><p>
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In 2 of 96 patients with adult-onset hemorrhagic stroke, Weng et al. (2012) identified different heterozygous mutations in the COL4A1 gene (120130.0015 and 120130.0016). The COL4A1 gene was chosen for study because mutation in this gene can cause rare familial forms of cerebrovascular disease. In vitro cellular studies showed that both mutant proteins were retained intracellularly and impaired normal COL4A1 secretion. </p>
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<strong>REFERENCES</strong>
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Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J., Valant, V., Greenberg, S. M., Rosand, J., Gould, D. B.
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<strong>COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.</strong>
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Am. J. Hum. Genet. 90: 91-101, 2012.
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[PubMed: 22209247]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.11.022]
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Slowik, A., Turaj, W., Dziedzic, T., Haefele, A., Pera, J., Malecki, M. T., Glodzik-Sobanska, L., Szermer, P., Figlewicz, D. A., Szczudlik, A.
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<strong>DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.</strong>
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Neurology 63: 359-361, 2004.
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[PubMed: 15277638]
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[Full Text: https://doi.org/10.1212/01.wnl.0000130200.12993.0c]
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Weng, Y.-C., Sonni, A., Labelle-Dumais, C., de Leau, M., Kauffman, W. B., Jeanne, M., Biffi, A., Greenberg, S. M., Rosand, J., Gould, D. B.
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<strong>COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.</strong>
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Ann. Neurol. 71: 470-477, 2012.
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[PubMed: 22522439]
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[Full Text: https://doi.org/10.1002/ana.22682]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/18/2012
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 3/5/2012
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Edit History:
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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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joanna : 06/29/2016<br>carol : 12/19/2012<br>ckniffin : 12/18/2012<br>carol : 3/7/2012<br>terry : 3/5/2012<br>ckniffin : 3/5/2012
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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