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Entry
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- #614495 - PSEUDOHYPOALDOSTERONISM, TYPE IID; PHA2D
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- OMIM
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<p>
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<span class="h4">#614495</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/614495"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS145260"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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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><a href="https://clinicaltrials.gov/search?cond=PSEUDOHYPOALDOSTERONISM, TYPE IID" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21125&Typ=Pat" title="Pseudohypoaldosteronism type 2D" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pseudohypoaldosteronism ty… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3723&Typ=Pat" title="Pseudohypoaldosteronism type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pseudohypoaldosteronism ty… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK65707/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/9187" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614495[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><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300525" title="Pseudohypoaldosteronism type 2D" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pseudohypoaldosteronism ty…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=757" title="Pseudohypoaldosteronism type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pseudohypoaldosteronism ty…</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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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>ORPHA:</strong> 300525, 757<br />
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">ICD+</a>
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<div>
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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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614495
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</span>
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</span>
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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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PSEUDOHYPOALDOSTERONISM, TYPE IID; PHA2D
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FAMILIAL HYPERKALEMIC HYPERTENSION; FHHT
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<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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<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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</thead>
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<tbody>
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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/5/493?start=-3&limit=10&highlight=493">
|
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5q31.2
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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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Pseudohypoaldosteronism, type IID
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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/614495"> 614495 </a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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KLHL3
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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/605775"> 605775 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/614495" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<a href="/phenotypicSeries/PS145260" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/614495" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/614495" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
|
|
Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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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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<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br />
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|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hyperchloremic metabolic acidosis (HCO3 17.2 +/- 2.5 mM, dominant) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281018&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281018</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P74.421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P74.421</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004918" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004918</a>]</span><br /> -
|
|
Hyperchloremic metabolic acidosis (HCO3 17.6 +/- 1.5 mM, recessive) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281019</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P74.421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P74.421</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004918" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004918</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hyperkalemia (>6.2 mM in both dominant and recessive) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3281010&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3281010</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238142003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238142003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14140009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14140009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166689004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166689004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/276.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">276.7</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002153" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002153</a>]</span><br /> -
|
|
Hyperchloremia (mean >110 mM in both dominant and recessive) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74450001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74450001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085679&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085679</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011423</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011423" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011423</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 40 patients in 16 dominant kindreds reported (as of February 2012)<br /> -
|
|
14 patients in 8 recessive kindreds reported (as of February 2012)<br /> -
|
|
Less than 20% have onset at 18 years of age or less (dominant and recessive)<br /> -
|
|
Age at diagnosis 24 +/- 18 years for dominant disease<br /> -
|
|
Age at diagnosis 26 +/- 14 years for recessive disease<br /> -
|
|
Responsive to thiazide diuretics<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the kelch-like 3 gene (KLHL3, <a href="/entry/605775#0001">605775.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Pseudohypoaldosteronism, type II
|
|
- <a href="/phenotypicSeries/PS145260">PS145260</a>
|
|
- 5 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1506?start=-3&limit=10&highlight=1506"> 1q31-q42 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/145260"> Pseudohypoaldosteronism, type IIA </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">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/145260"> 145260 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/145260"> PHA2A </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/145260"> 145260 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/1065?start=-3&limit=10&highlight=1065"> 2q36.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614496"> Pseudohypoaldosteronism, type IIE </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">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614496"> 614496 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603136"> CUL3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603136"> 603136 </a>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because pseudohypoaldosteronism type IID (PHA2D) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the KLHL3 gene (<a href="/entry/605775">605775</a>) on chromosome 5q31.</p>
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<p>Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by <a href="#2" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" 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>Genetic Heterogeneity of Type II Pseudohypoaldosteronism</em></strong></p><p>
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For a discussion of genetic heterogeneity of type II pseudohypoaldosteronism, see PHA2A (<a href="/entry/145260">145260</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> studied a cohort of 52 PHAII kindreds including 126 affected subjects with renal hyperkalemia and otherwise normal renal function; hypertension and acidosis were present in 71% and 82%, respectively. Among these 52 kindreds, 8 kindreds including 14 individuals carried recessive mutations in KLHL3, and 16 kindreds including 40 individuals carried dominant mutations. The phenotype of patients carrying either type of mutation was similar. The mean age at diagnosis or referral among patients with recessive mutations was 26 +/- 14 years. They had a mean potassium at time of diagnosis of 6.8 +/- 0.5; mean bicarbonate was 17.6 +/- 1.5; and only 14% had developed hypertension by 18 years of age. Among the patients with dominant mutations, mean age at diagnosis or referral was 24 +/- 18 years, mean potassium 6.2 +/- 0.6 mM, and mean bicarbonate 17.2 +/- 2.5; 17% had hypertension diagnosed by age 18 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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>Thiazide diuretics correct abnormalities in virtually all PHAII subjects (<a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> performed exome sequencing of 11 unrelated PHAII index cases without WNK mutations and identified novel KLHL3 mutations comprising 5 alleles in 3 kindreds, all of which cosegregated with the trait. <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> identified 1 kindred in which affected members were homozygous for a nonsense mutation (<a href="/entry/605775#0001">605775.0001</a>), 1 in which affected members are compound heterozygous for 2 missense mutations (<a href="/entry/605775#0002">605775.0002</a>, <a href="/entry/605775#0003">605775.0003</a>), and 1 segregating a heterozygous missense mutation (<a href="/entry/605775#0004">605775.0004</a>). As a confirmation of significance, Fisher exact test was used to compare the prevalence of novel protein-altering variants in all genes in PHAII cases versus 699 control exomes. The KLHL3 gene showed a burden of mutation that surpassed genomewide significance (P = 1.1 x 10(-8)). The KLHL3 gene was sequenced in all PHAII index cases, and novel mutations were identified in 24. Nearly all were at positions conserved among orthologs. Sixteen kindreds had heterozygous mutations that cosegregated with the trait under a dominant model (lod score = 6.9, less than -2 under other models). In contrast, 8 index cases inherited mutations in both KLHL3 alleles. In these kindreds, affected members were confined to sibs of index cases who inherited the same 2 mutations, whereas unaffected relatives inherited zero or 1 mutation (lod score 4.3 for a recessive model, less than -2 for other models). This was the first report of recessive transmission for PHAII. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> observed that, consistent with 2 modes of transmission, subjects with dominant KLHL3 mutations had significantly higher serum potassium levels (6.2 +/- 0.6 mM) than heterozygotes for recessive mutations (4.8 +/- 0.6 mM) (P less than 10(-4), Student's t-test; normal range 3.5-5.0 mM). <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> concluded that PHAII can be caused by either recessive or dominant KLHL3 mutations, and inferred that mutations in dominant kindreds are probably dominant-negative because they phenocopy the features of recessive disease. While recessive KLHL3 mutations were distributed throughout the encoded protein, dominant KLHL3 mutations showed marked clustering. Nine of 16 dominant mutations altered 1 of the last 4 amino acids of the 6 'd-a' loops that connect the outermost (d) beta-strand of 1 kelch propeller blade to the innermost (a) beta-strand of the next blade. Two others were in 'b-c' loops. These dominant PHAH mutations lay near the hub of the propeller at or near sites implicated in substrate binding in paralogs. Three other dominant mutations clustered within the BTB domain, at or near sites implicated in cullin binding in paralogs. <a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> inferred that dominant mutations in KLHL3 probably impair binding either to specific substrates or to CUL3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 3-generation French family with hyperkalemic hypertension, <a href="#2" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> performed whole-exome sequencing in 1 unaffected and 3 affected family members and identified a heterozygous missense mutation in the KLHL3 gene (R528H; <a href="/entry/605775#0004">605775.0004</a>) that segregated with disease. A larger, 4-generation French family with a milder phenotype, in which only 3 of 14 affected individuals with hyperkalemia also had hypertension, showed linkage to chromosome 5q31 and was found to harbor a different heterozygous missense mutation in KLHL3 (A398V; <a href="/entry/605775#0010">605775.0010</a>) that segregated with disease. Analysis of KLHL3 in 43 probands with FHHT revealed 8 families in which a heterozygous missense mutation segregated with disease (see, e.g., <a href="/entry/605775#0003">605775.0003</a>, <a href="/entry/605775#0008">605775.0008</a>, and <a href="/entry/605775#0011">605775.0011</a>), as well as 4 consanguineous cases in which a homozygous missense mutation was found (see, e.g., <a href="/entry/605775#0012">605775.0012</a>). On average, the recessive cases were diagnosed at an earlier age (2.5 months to 17 years) than those with heterozygous mutations (15 to 56 years) and had a more severe phenotype. Screening of the KLHL3 gene in 1,232 individuals with essential hypertension (see <a href="/entry/145000">145000</a>) revealed only 1 deleterious mutation in a hypertensive patient with mild hyperkalemia; <a href="#2" class="mim-tip-reference" title="Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others. <strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong> Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>] [<a href="https://doi.org/10.1038/ng.2218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22406640">Louis-Dit-Picard et al. (2012)</a> concluded that missense mutations causing hyperkalemic hypertension are rare in the general hypertensive population of European descent. No KLHL3 mutations were found in 800 normotensive individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. <strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong> Nature 482: 98-102, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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/nature10814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22266938">Boyden et al. (2012)</a> observed that families with PHAII due to mutation in the WNK1 gene (PHA2C; <a href="/entry/614492">614492</a>) are significantly less severely affected than those with mutation in WNK4 (PHA2B; <a href="/entry/614491">614491</a>) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutations in the CUL3 gene (<a href="/entry/603136">603136</a>; PHA2E, <a href="/entry/614496">614496</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22266938" 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 transgenic mice, <a href="#3" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> found that heterozygous expression of human KLHL3 with the arg528-to-his (R528H; <a href="/entry/605775#0004">605775.0004</a>) mutation caused a high salt-dependent elevation in systolic blood pressure compared with control mice or KLHL3(R528H/+) mice on a low-salt diet. Transgenic KLHL3(R528H/+) mice also showed hyperkalemia and metabolic acidosis under both low- and high-salt conditions. Homozygous KLHL3(R528H/R528H) mice showed similar salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. <a href="#3" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> concluded that the KLHL3(R528H/+) mouse is a model of PHA2D. KLHL3(R528H/+) mice had elevated renal expression of the kinases Wnk1 (<a href="/entry/605232">605232</a>) and Wnk4 (<a href="/entry/601844">601844</a>) in distal convoluted tubules, resulting in increased phosphorylation of the Wnk targets Osr1 (OXSR1; <a href="/entry/604046">604046</a>) and Spak (STK39; <a href="/entry/607648">607648</a>) and of the sodium-chloride channel Ncc (SLC12A3; <a href="/entry/600968">600968</a>). <a href="#3" class="mim-tip-reference" title="Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S. <strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong> Hum. Molec. Genet. 23: 5052-5060, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>] [<a href="https://doi.org/10.1093/hmg/ddu217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24821705">Susa et al. (2014)</a> proposed that the R528H mutation interferes with binding of KLHL3 to WNK1 and WNK4, impairing ubiquitination and degradation of the kinases and resulting in activation of a phosphorylation cascade that elevates activity of sodium channels, such as ENaC (see <a href="/entry/600228">600228</a>), and sodium-chloride channels, such as NCC, at the distal convoluted tubule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" 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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Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others.
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<strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong>
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Nature 482: 98-102, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22266938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22266938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22266938[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=22266938" 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/nature10814" target="_blank">Full Text</a>]
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Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others.
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<strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong>
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Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22406640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22406640</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22406640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2218" target="_blank">Full Text</a>]
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Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S.
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<strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong>
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Hum. Molec. Genet. 23: 5052-5060, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24821705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24821705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24821705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Patricia A. Hartz - updated : 10/28/2014
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carol : 02/09/2018<br>mgross : 11/24/2014<br>mgross : 10/28/2014<br>carol : 5/14/2012<br>alopez : 2/27/2012
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<span class="mim-font">
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<strong>#</strong> 614495
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PSEUDOHYPOALDOSTERONISM, TYPE IID; PHA2D
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FAMILIAL HYPERKALEMIC HYPERTENSION; FHHT
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<strong>ORPHA:</strong> 300525, 757;
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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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5q31.2
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Pseudohypoaldosteronism, type IID
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614495
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Autosomal dominant; Autosomal recessive
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<span class="mim-font">
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3
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KLHL3
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605775
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because pseudohypoaldosteronism type IID (PHA2D) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the KLHL3 gene (605775) on chromosome 5q31.</p>
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<strong>Description</strong>
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<p>Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by Louis-Dit-Picard et al., 2012). </p><p><strong><em>Genetic Heterogeneity of Type II Pseudohypoaldosteronism</em></strong></p><p>
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For a discussion of genetic heterogeneity of type II pseudohypoaldosteronism, see PHA2A (145260).</p>
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<p>Boyden et al. (2012) studied a cohort of 52 PHAII kindreds including 126 affected subjects with renal hyperkalemia and otherwise normal renal function; hypertension and acidosis were present in 71% and 82%, respectively. Among these 52 kindreds, 8 kindreds including 14 individuals carried recessive mutations in KLHL3, and 16 kindreds including 40 individuals carried dominant mutations. The phenotype of patients carrying either type of mutation was similar. The mean age at diagnosis or referral among patients with recessive mutations was 26 +/- 14 years. They had a mean potassium at time of diagnosis of 6.8 +/- 0.5; mean bicarbonate was 17.6 +/- 1.5; and only 14% had developed hypertension by 18 years of age. Among the patients with dominant mutations, mean age at diagnosis or referral was 24 +/- 18 years, mean potassium 6.2 +/- 0.6 mM, and mean bicarbonate 17.2 +/- 2.5; 17% had hypertension diagnosed by age 18 years. </p>
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<strong>Clinical Management</strong>
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<p>Thiazide diuretics correct abnormalities in virtually all PHAII subjects (Boyden et al., 2012). </p>
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<strong>Molecular Genetics</strong>
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<p>Boyden et al. (2012) performed exome sequencing of 11 unrelated PHAII index cases without WNK mutations and identified novel KLHL3 mutations comprising 5 alleles in 3 kindreds, all of which cosegregated with the trait. Boyden et al. (2012) identified 1 kindred in which affected members were homozygous for a nonsense mutation (605775.0001), 1 in which affected members are compound heterozygous for 2 missense mutations (605775.0002, 605775.0003), and 1 segregating a heterozygous missense mutation (605775.0004). As a confirmation of significance, Fisher exact test was used to compare the prevalence of novel protein-altering variants in all genes in PHAII cases versus 699 control exomes. The KLHL3 gene showed a burden of mutation that surpassed genomewide significance (P = 1.1 x 10(-8)). The KLHL3 gene was sequenced in all PHAII index cases, and novel mutations were identified in 24. Nearly all were at positions conserved among orthologs. Sixteen kindreds had heterozygous mutations that cosegregated with the trait under a dominant model (lod score = 6.9, less than -2 under other models). In contrast, 8 index cases inherited mutations in both KLHL3 alleles. In these kindreds, affected members were confined to sibs of index cases who inherited the same 2 mutations, whereas unaffected relatives inherited zero or 1 mutation (lod score 4.3 for a recessive model, less than -2 for other models). This was the first report of recessive transmission for PHAII. </p><p>Boyden et al. (2012) observed that, consistent with 2 modes of transmission, subjects with dominant KLHL3 mutations had significantly higher serum potassium levels (6.2 +/- 0.6 mM) than heterozygotes for recessive mutations (4.8 +/- 0.6 mM) (P less than 10(-4), Student's t-test; normal range 3.5-5.0 mM). Boyden et al. (2012) concluded that PHAII can be caused by either recessive or dominant KLHL3 mutations, and inferred that mutations in dominant kindreds are probably dominant-negative because they phenocopy the features of recessive disease. While recessive KLHL3 mutations were distributed throughout the encoded protein, dominant KLHL3 mutations showed marked clustering. Nine of 16 dominant mutations altered 1 of the last 4 amino acids of the 6 'd-a' loops that connect the outermost (d) beta-strand of 1 kelch propeller blade to the innermost (a) beta-strand of the next blade. Two others were in 'b-c' loops. These dominant PHAH mutations lay near the hub of the propeller at or near sites implicated in substrate binding in paralogs. Three other dominant mutations clustered within the BTB domain, at or near sites implicated in cullin binding in paralogs. Boyden et al. (2012) inferred that dominant mutations in KLHL3 probably impair binding either to specific substrates or to CUL3. </p><p>In a 3-generation French family with hyperkalemic hypertension, Louis-Dit-Picard et al. (2012) performed whole-exome sequencing in 1 unaffected and 3 affected family members and identified a heterozygous missense mutation in the KLHL3 gene (R528H; 605775.0004) that segregated with disease. A larger, 4-generation French family with a milder phenotype, in which only 3 of 14 affected individuals with hyperkalemia also had hypertension, showed linkage to chromosome 5q31 and was found to harbor a different heterozygous missense mutation in KLHL3 (A398V; 605775.0010) that segregated with disease. Analysis of KLHL3 in 43 probands with FHHT revealed 8 families in which a heterozygous missense mutation segregated with disease (see, e.g., 605775.0003, 605775.0008, and 605775.0011), as well as 4 consanguineous cases in which a homozygous missense mutation was found (see, e.g., 605775.0012). On average, the recessive cases were diagnosed at an earlier age (2.5 months to 17 years) than those with heterozygous mutations (15 to 56 years) and had a more severe phenotype. Screening of the KLHL3 gene in 1,232 individuals with essential hypertension (see 145000) revealed only 1 deleterious mutation in a hypertensive patient with mild hyperkalemia; Louis-Dit-Picard et al. (2012) concluded that missense mutations causing hyperkalemic hypertension are rare in the general hypertensive population of European descent. No KLHL3 mutations were found in 800 normotensive individuals. </p>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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<span class="mim-text-font">
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<p>Boyden et al. (2012) observed that families with PHAII due to mutation in the WNK1 gene (PHA2C; 614492) are significantly less severely affected than those with mutation in WNK4 (PHA2B; 614491) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutations in the CUL3 gene (603136; PHA2E, 614496). </p>
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<strong>Animal Model</strong>
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<p>Using transgenic mice, Susa et al. (2014) found that heterozygous expression of human KLHL3 with the arg528-to-his (R528H; 605775.0004) mutation caused a high salt-dependent elevation in systolic blood pressure compared with control mice or KLHL3(R528H/+) mice on a low-salt diet. Transgenic KLHL3(R528H/+) mice also showed hyperkalemia and metabolic acidosis under both low- and high-salt conditions. Homozygous KLHL3(R528H/R528H) mice showed similar salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. Susa et al. (2014) concluded that the KLHL3(R528H/+) mouse is a model of PHA2D. KLHL3(R528H/+) mice had elevated renal expression of the kinases Wnk1 (605232) and Wnk4 (601844) in distal convoluted tubules, resulting in increased phosphorylation of the Wnk targets Osr1 (OXSR1; 604046) and Spak (STK39; 607648) and of the sodium-chloride channel Ncc (SLC12A3; 600968). Susa et al. (2014) proposed that the R528H mutation interferes with binding of KLHL3 to WNK1 and WNK4, impairing ubiquitination and degradation of the kinases and resulting in activation of a phosphorylation cascade that elevates activity of sodium channels, such as ENaC (see 600228), and sodium-chloride channels, such as NCC, at the distal convoluted tubule. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others.
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<strong>Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.</strong>
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Nature 482: 98-102, 2012.
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[PubMed: 22266938]
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[Full Text: https://doi.org/10.1038/nature10814]
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Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., Beaurain, G., Bonnefond, A., Sand, O., Simian, C., Vidal-Petiot, E., Soukaseum, C., and 27 others.
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<strong>KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.</strong>
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Nature Genet. 44: 456-460, 2012. Note: Erratum: Nature Genet. 44: 609 only, 2012.
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[PubMed: 22406640]
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[Full Text: https://doi.org/10.1038/ng.2218]
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Susa, K., Sohara, E., Rai, T., Zeniya, M., Mori, Y., Mori, T., Chiga, M., Nomura, N., Nishida, H., Takahashi, D., Isobe, K., Inoue, Y., Takeishi, K., Takeda, N., Sasaki, S., Uchida, S.
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<strong>Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice.</strong>
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Hum. Molec. Genet. 23: 5052-5060, 2014.
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[PubMed: 24821705]
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[Full Text: https://doi.org/10.1093/hmg/ddu217]
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div 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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Patricia A. Hartz - updated : 10/28/2014<br>Marla J. F. O'Neill - updated : 5/14/2012
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Creation Date:
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Ada Hamosh : 2/24/2012
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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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carol : 07/09/2019<br>carol : 02/09/2018<br>mgross : 11/24/2014<br>mgross : 10/28/2014<br>carol : 5/14/2012<br>alopez : 2/27/2012
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