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Entry
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- *136850 - FUMARATE HYDRATASE; FH
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- OMIM
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<p>
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<span class="h4">*136850</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/136850">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000091483;t=ENST00000366560" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2271" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=136850" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000091483;t=ENST00000366560" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000143" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000143" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=136850" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00652&isoform_id=00652_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/FH" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/182794,1545996,4097195,13111881,16924307,19743875,31747342,32880021,119590496,119590497,119590498,119590499,189065486,308219936,957949411,957949414,957949417,957949420,957949423,957949426,1812588806" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P07954" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2271" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000091483;t=ENST00000366560" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=FH" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=FH" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2271" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/FH" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2271" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2271" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000366560.4&hgg_start=241497603&hgg_end=241519755&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3700" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3700" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/fh" 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=136850[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=136850[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FH/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000091483" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=FH" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FH" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/FH" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FH&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA28139" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3700" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0029890.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95530" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/FH#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95530" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2271/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2271" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001503;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-010724-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:136850" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2271" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FH&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1162799008, 237983002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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136850
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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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FUMARATE HYDRATASE; FH
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FUMARASE
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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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<a id="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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FUMARATE HYDRATASE, CYTOSOLIC, INCLUDED; FH1, INCLUDED
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</span>
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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FUMARATE HYDRATASE, MITOCHONDRIAL, INCLUDED; FH2, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FH" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FH</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1836?start=-3&limit=10&highlight=1836">1q43</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:241497603-241519755&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:241,497,603-241,519,755</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=606812,150800" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
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<span class="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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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Fumarate hydratase, or fumarase (<a href="https://enzyme.expasy.org/EC/4.2.1.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 4.2.1.2</a>), is an enzymatic component of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion of fumarate to malate.</p>
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<p><a href="#13" class="mim-tip-reference" title="Edwards, Y. H., Hopkinson, D. A. <strong>The genetic determination of fumarase isozymes in human tissues.</strong> Ann. Hum. Genet. 42: 303-313, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/434773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">434773</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1979.tb00664.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="434773">Edwards and Hopkinson (1979)</a> studied a family with an electrophoretic variant of FH. Two persons had variation in both the soluble and the mitochondrial forms, suggesting that they are determined by a single locus. <a href="#11" class="mim-tip-reference" title="Doonan, S., Barra, D., Bossa, F. <strong>Structural and genetic relationships between cytosolic and mitochondrial isoenzymes.</strong> Int. J. Biochem. 16: 1193-1199, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6397370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6397370</a>] [<a href="https://doi.org/10.1016/0020-711x(84)90216-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6397370">Doonan et al. (1984)</a> cited evidence suggesting that the isoenzymes of fumarase are translated in precursor form from 2 different mRNA molecules, these mRNAs in turn arising from alternative splicing of a single gene transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6397370+434773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using peptide mapping, <a href="#24" class="mim-tip-reference" title="O'Hare, M. C., Doonan, S. <strong>Purification and structural comparisons of the cytosolic and mitochondrial isoenzymes of fumarase from pig liver.</strong> Biochim. Biophys. Acta 827: 127-134, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3967032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3967032</a>] [<a href="https://doi.org/10.1016/0167-4838(85)90080-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3967032">O'Hare and Doonan (1985)</a> showed that the cytosolic and mitochondrial fumarases from pig liver are identical over nearly all of their amino acid sequences, but that they differ at their N termini. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3967032" 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="#19" class="mim-tip-reference" title="Kinsella, B. T., Doonan, S. <strong>Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver.</strong> Biosci. Rep. 6: 921-929, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3828494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3828494</a>] [<a href="https://doi.org/10.1007/BF01116247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3828494">Kinsella and Doonan (1986)</a> cloned human fumarase from a liver cDNA library. The deduced 468-amino acid protein, with the exception of an N-terminal methionine, appeared to be the mitochondrial form. <a href="#19" class="mim-tip-reference" title="Kinsella, B. T., Doonan, S. <strong>Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver.</strong> Biosci. Rep. 6: 921-929, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3828494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3828494</a>] [<a href="https://doi.org/10.1007/BF01116247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3828494">Kinsella and Doonan (1986)</a> found an unusually high degree of identity of structure between human fumarase and that from B. subtilis and E. coli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3828494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Suzuki, T., Sato, M., Yoshida, T., Tuboi, S. <strong>Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single gene.</strong> J. Biol. Chem. 264: 2581-2588, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2914923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2914923</a>]" pmid="2914923">Suzuki et al. (1989)</a> cloned rat liver fumarase, which encodes a deduced 507-amino acid protein with a 41-amino acid prosequence. Comparison of mature peptide sequences of mitochondrial and cytosolic fumarases revealed identity, with the exception that the N-terminal alanine of cytosolic fumarase was acetylated. Northern blot analysis of rat liver showed a single mRNA species of about 1.8 kb. <a href="#28" class="mim-tip-reference" title="Suzuki, T., Sato, M., Yoshida, T., Tuboi, S. <strong>Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single gene.</strong> J. Biol. Chem. 264: 2581-2588, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2914923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2914923</a>]" pmid="2914923">Suzuki et al. (1989)</a> concluded that the mitochondrial and cytosolic forms of fumarase are encoded by a single transcript and that posttranslational processing directs its cellular localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2914923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunohistochemical analysis, <a href="#3" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P. <strong>Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.</strong> J. Clin. Invest. 93: 2514-2518, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8200987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8200987</a>] [<a href="https://doi.org/10.1172/JCI117261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8200987">Bourgeron et al. (1994)</a> found that fumarase localized to the mitochondrion, but not cytosol, in normal human brain, consistent with the findings in rat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8200987" 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="#33" class="mim-tip-reference" title="van Someren, H., Beyersbergen van Henegouwen, H., de Wit, J. <strong>Evidence for synteny between the human loci for fumarate hydratase, UDG glucose pyrophosphorylase, 6-phosphogluconate dehydrogenase, phosphoglucomutase-1, and peptidase-C in man-Chinese hamster somatic cell hybrids.</strong> Cytogenet. Cell Genet. 13: 150-152, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4827484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4827484</a>] [<a href="https://doi.org/10.1159/000130273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4827484">Van Someren et al. (1974)</a> and <a href="#9" class="mim-tip-reference" title="Craig, I., Tolley, E., Bobrow, M. <strong>Mitochondrial and cytoplasmic forms of fumarate hydratase assigned to chromosome 1.</strong> Cytogenet. Cell Genet. 16: 118-121, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/975868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">975868</a>] [<a href="https://doi.org/10.1159/000130569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="975868">Craig et al. (1976)</a> found that the fumarase locus is on chromosome 1, possibly in the area 1q42. <a href="#10" class="mim-tip-reference" title="Despoisses, S., Noel, L., Choiset, A., Portnoi, M.-F., Turleau, C., Quack, B., Taillemite, J.-L., de Grouchy, J., Junien, C. <strong>Regional mapping of FH to band 1q42.1 by gene dosage studies. (Abstract)</strong> Cytogenet. Cell Genet. 37: 450-451, 1984."None>Despoisses et al. (1984)</a> narrowed the regional assignment of FH to 1q42.1 by gene dosage studies in patients with various types of partial trisomy or partial monosomy of 1q. <a href="#8" class="mim-tip-reference" title="Coughlin, E. M., Chalmers, R. A., Slaugenhaupt, S. A., Gusella, J. F., Shih, V. E., Ramesh, V. <strong>Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993."None>Coughlin et al. (1993)</a> mapped the FH gene to chromosome 1 using PCR-amplified cDNA as a probe in Southern blots of genomic DNA from a series of mouse/human somatic cell hybrids. They observed related sequences on chromosomes 13 and 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=975868+4827484" 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="#26" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase and succinate dehydrogenases (see, e.g., SDHB <a href="/entry/185470">185470</a>) act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer and to paragangliomas (see <a href="/entry/115310">115310</a>), respectively. <a href="#26" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (<a href="/entry/603348">603348</a>), activation of HIF1A targets like VEGF (<a href="/entry/192240">192240</a>), and high microvessel density. <a href="#26" class="mim-tip-reference" title="Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., and 9 others. <strong>Accumulation of Krebs cycle intermediates and over-expression of HIF1-alpha in tumours which result from germline FH and SDH mutations.</strong> Hum. Molec. Genet. 14: 2231-2239, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15987702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15987702</a>] [<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15987702">Pollard et al. (2005)</a> hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paragangliomas and leiomyoma and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (<a href="/entry/193300">193300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15987702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Fh -/- mouse embryonic fibroblasts and FH-deficient papillary renal carcinoma tissues, <a href="#23" class="mim-tip-reference" title="O'Flaherty, L., Adam, J., Heather, L. C., Zhdanov, A. V., Chung, Y.-L., Miranda, M. X., Croft, J., Olpin, S., Clarke, K., Pugh, C. W., Griffiths, J., Papkovsky, D., Ashrafian, H., Ratcliffe, P. J., Pollard, P. J. <strong>Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism.</strong> Hum. Molec. Genet. 19: 3844-3851, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660115</a>] [<a href="https://doi.org/10.1093/hmg/ddq305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660115">O'Flaherty et al. (2010)</a> showed that deficiency in cytosolic fumarase directly led to HIF1-alpha activation. As expected, Fh -/- mouse cells showed elevated fumarate accumulation and lactate production, and reduced cellular respiration. Fh -/- also showed upregulated Hif1-alpha transcriptional activity due to reduced Hif1-alpha prolyl hydroxylation. Profound dysregulation of HIF1-alpha also occurred in FH-associated neoplasias. Reintroduction of wildtype human FH lacking the mitochondrial targeting sequence largely ablated fumarate accumulation and restored HIF1-alpha prolyl hydroxylation and inactivation without restoration of mitochondrial respiration. <a href="#23" class="mim-tip-reference" title="O'Flaherty, L., Adam, J., Heather, L. C., Zhdanov, A. V., Chung, Y.-L., Miranda, M. X., Croft, J., Olpin, S., Clarke, K., Pugh, C. W., Griffiths, J., Papkovsky, D., Ashrafian, H., Ratcliffe, P. J., Pollard, P. J. <strong>Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism.</strong> Hum. Molec. Genet. 19: 3844-3851, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660115</a>] [<a href="https://doi.org/10.1093/hmg/ddq305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660115">O'Flaherty et al. (2010)</a> proposed that fumarate is a catalytic inhibitor of HIF1-alpha prolyl hydroxylation, and that fumarase deficiency may mimic hypoxia, resulting in HIF1-alpha activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using genetically modified mouse kidney cells in which Fh1 had been deleted, <a href="#14" class="mim-tip-reference" title="Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. P. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., Gottlieb, E. <strong>Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.</strong> Nature 477: 225-228, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21849978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21849978</a>] [<a href="https://doi.org/10.1038/nature10363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21849978">Frezza et al. (2011)</a> applied a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of heme, enables Fh1-deficient cells to use accumulated tricarboxylic acid (TCA) cycle metabolites and permits partial mitochondrial NADH production. <a href="#14" class="mim-tip-reference" title="Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. P. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., Gottlieb, E. <strong>Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.</strong> Nature 477: 225-228, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21849978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21849978</a>] [<a href="https://doi.org/10.1038/nature10363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21849978">Frezza et al. (2011)</a> predicted and confirmed that targeting this pathway would render Fh1-deficient cells nonviable, while sparing wildtype Fh1-containing cells. <a href="#14" class="mim-tip-reference" title="Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. P. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., Gottlieb, E. <strong>Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.</strong> Nature 477: 225-228, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21849978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21849978</a>] [<a href="https://doi.org/10.1038/nature10363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21849978">Frezza et al. (2011)</a> concluded that their work went beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of heme oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a potential target for treating HLRCC (<a href="/entry/150800">150800</a>) patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21849978" 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>Fumarase Deficiency</em></strong></p><p>
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In patients with fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>), Bourgeron et al. (<a href="#4" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Rotig, A., Munnich, A., Landrieu, P., Rustin, P. <strong>Molecular characterization of fumarase deficiency in two children with progressive encephalopathy. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A891 only, 1993."None>1993</a>, <a href="#3" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P. <strong>Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.</strong> J. Clin. Invest. 93: 2514-2518, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8200987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8200987</a>] [<a href="https://doi.org/10.1172/JCI117261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8200987">1994</a>) and <a href="#8" class="mim-tip-reference" title="Coughlin, E. M., Chalmers, R. A., Slaugenhaupt, S. A., Gusella, J. F., Shih, V. E., Ramesh, V. <strong>Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993."None>Coughlin et al. (1993)</a> identified mutations in the FH gene (<a href="#0001">136850.0001</a> and <a href="#0002">136850.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8200987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters with an attenuated form of FMRD, <a href="#27" class="mim-tip-reference" title="Prasad, C., Napier, M. P., Rupar, C. A., Prasad, C. <strong>Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer.</strong> Clin. Dysmorph. 26: 117-120, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27541980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27541980</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27541980">Prasad et al. (2017)</a> identified compound heterozygous mutations in the FH gene: a duplication (K477dup; <a href="#0012">136850.0012</a>) and a splice site mutation (<a href="#0013">136850.0013</a>). The sibs had no encephalopathy and near-normal urine fumaric acid levels. The mutations segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27541980" 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 patient with FMRD, <a href="#16" class="mim-tip-reference" title="Grocott, O., Phanor, S. K., Fung, F., Thibert, R. L., Berkmen, M. B. <strong>Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.</strong> Am. J. Med. Genet. 182A: 504-507, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31746132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31746132</a>] [<a href="https://doi.org/10.1002/ajmg.a.61415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31746132">Grocott et al. (2020)</a> identified compound heterozygous mutations in the FH gene (D65G, <a href="#0014">136850.0014</a>; c.1293delA, <a href="#0015">136850.0015</a>). Fumarase enzyme was purified from plasmids containing FH with each of the patient's mutations. Fumarase with the c.1293delA mutation had defective enzyme activity and oligomerization. Fumarase with the D65G mutation had a lower catalytic activity compared to wildtype. Urine organic acids in the patient demonstrated elevated fumaric acid, and cytosolic and mitochondrial fumarase enzyme activities were decreased in patient fibroblasts. The patient had seizures, hypotonia, and developmental delay but survived until 16 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31746132" 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>Hereditary Leiomyomatosis and Renal Cell Cancer</em></strong></p><p>
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In patients with hereditary leiomyomatosis and renal cell cancer (HRLCC; <a href="/entry/150800">150800</a>), <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> identified several heterozygous mutations in the FH gene (<a href="#0005">136850.0005</a> and <a href="#0006">136850.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In patients with multiple cutaneous and uterine leiomyomata, <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> identified heterozygous mutations in the FH gene (<a href="#0003">136850.0003</a> and <a href="#0004">136850.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using sequence analysis, <a href="#31" class="mim-tip-reference" title="Toro, J. R., Nickerson, M. L., Wei, M.-H., Warren, M. B., Glenn, G. M., Turner, M. L., Stewart, L., Duray, P., Tourre, O., Sharma, N., Choyke, P., Stratton, P., Merino, M., Walther, M. M., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.</strong> Am. J. Hum. Genet. 73: 95-106, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12772087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12772087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12772087[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/10.1086/376435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12772087">Toro et al. (2003)</a> identified germline mutations in the FH gene in 31 of 35 (89%) families with cutaneous leiomyomas. Eighteen of the 20 different mutations they identified-- 2 insertions, 5 small deletions that caused frameshifts leading to premature termination of the protein, and 13 missense--were novel. The same mutation, arg190 to his (R190H; <a href="#0007">136850.0007</a>), was identified in 11 unrelated families. Cutaneous leiomyomas were found in 81 individuals (47 women and 34 men). Uterine leiomyomas were also found in 98% (46 of 47) of women with cutaneous leiomyomas. Total hysterectomy was performed in 89% (41 of 46) of women with cutaneous and uterine leiomyomas, 44% before or at age 30 years. In 13 individuals in 5 families, <a href="#31" class="mim-tip-reference" title="Toro, J. R., Nickerson, M. L., Wei, M.-H., Warren, M. B., Glenn, G. M., Turner, M. L., Stewart, L., Duray, P., Tourre, O., Sharma, N., Choyke, P., Stratton, P., Merino, M., Walther, M. M., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.</strong> Am. J. Hum. Genet. 73: 95-106, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12772087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12772087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12772087[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/10.1086/376435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12772087">Toro et al. (2003)</a> identified unilateral and solitary renal tumors. Papillary type II renal cell carcinoma was present in 7 individuals from 4 families, and another individual from 1 of these families had collecting duct carcinoma of the kidney. The study expanded the histologic spectrum of renal tumors and FH mutations associated with hereditary leiomyomatosis and renal cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12772087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Barker, K. T., Bevan, S., Wang, R., Lu, Y.-J., Flanagan, A. M., Bridge, J. A., Fisher, C., Finlayson, C. J., Shipley, J., Houlston, R. S. <strong>Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.</strong> Brit. J. Cancer 87: 446-448, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12177782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12177782</a>] [<a href="https://doi.org/10.1038/sj.bjc.660502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12177782">Barker et al. (2002)</a> analyzed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harbored somatic mutations in fumarate hydratase. Only 5% (7 of 129) of the leiomyomas showed allele imbalance at 1q42-q43, and no somatic mutations in fumarate hydratase were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12177782" 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="Alam, N. A., Rowan, A. J., Wortham, N. C., Pollard, P. J., Mitchell, M., Tyrer, J. P., Barclay, E., Calonje, E., Manek, S., Adams, S. J., Bowers, P. W., Burrows, N. P., and 18 others. <strong>Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.</strong> Hum. Molec. Genet. 12: 1241-1252, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12761039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12761039</a>] [<a href="https://doi.org/10.1093/hmg/ddg148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12761039">Alam et al. (2003)</a> reported 20 FH mutations in 35 of 46 probands with multiple cutaneous and uterine leiomyomata (MCUL) or FH deficiency. Disease-associated missense FH changes mapped to highly conserved residues, mostly in or around the enzyme's active site or activation site. The mutation spectra in FH deficiency and MCUL were similar, although in the latter mutations tended to occur more 5-prime in the gene and were predicted to result in a truncated or absent protein. The authors reported that not all mutation-carrier parents of FH deficiency children had a strong predisposition to leiomyomata. Renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome; these cancers may have either type II papillary or collecting duct morphology. There was no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients may indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. The authors concluded that MCUL is probably a genetically homogeneous tumor predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12761039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether FH mutations may predispose women to developing nonsyndromic uterine leiomyomas (UL; <a href="/entry/150699">150699</a>), <a href="#17" class="mim-tip-reference" title="Gross, K. L., Panhuysen, C. I. M., Kleinman, M. S., Goldhammer, H., Jones, E. S., Nassery, N., Stewart, E. A., Morton, C. C. <strong>Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.</strong> Genes Chromosomes Cancer 41: 183-190, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15334541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15334541</a>] [<a href="https://doi.org/10.1002/gcc.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15334541">Gross et al. (2004)</a> performed a genetic linkage study with DNA from 123 families containing at least 1 affected sister pair. In addition, to assess the frequency of FH loss specifically in uterine leiomyomas with 1q rearrangements, they performed a FISH analysis of UL. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (p = 0.04). FISH results showed that 1 copy of FH was absent in 9 of 11 ULs. <a href="#17" class="mim-tip-reference" title="Gross, K. L., Panhuysen, C. I. M., Kleinman, M. S., Goldhammer, H., Jones, E. S., Nassery, N., Stewart, E. A., Morton, C. C. <strong>Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.</strong> Genes Chromosomes Cancer 41: 183-190, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15334541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15334541</a>] [<a href="https://doi.org/10.1002/gcc.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15334541">Gross et al. (2004)</a> concluded that loss of FH may be a significant event in the pathogenesis of a subset of nonsyndromic ULs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15334541" 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>Because some individuals with HLRCC with a germline FH mutation have breast cancer (<a href="/entry/114480">114480</a>), <a href="#20" class="mim-tip-reference" title="Kiuru, M., Lehtonen, R., Eerola, H., Aittomaki, K., Blomqvist, C., Nevanlinna, H., Aaltonen, L. A., Launonen, V. <strong>No germline FH mutations in familial breast cancer patients.</strong> Europ. J. Hum. Genet. 13: 506-509, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523491</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523491">Kiuru et al. (2005)</a> analyzed germline FH mutations from 85 Finnish breast cancer patients, most of whom were selected based on positive family or personal history for malignancies associated with HLRCC. No mutations were found. <a href="#20" class="mim-tip-reference" title="Kiuru, M., Lehtonen, R., Eerola, H., Aittomaki, K., Blomqvist, C., Nevanlinna, H., Aaltonen, L. A., Launonen, V. <strong>No germline FH mutations in familial breast cancer patients.</strong> Europ. J. Hum. Genet. 13: 506-509, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523491</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523491">Kiuru et al. (2005)</a> concluded that FH is not a major predisposing gene for familial breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523491" 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="#34" class="mim-tip-reference" title="Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R. <strong>Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.</strong> J. Med. Genet. 43: 18-27, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937070[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/10.1136/jmg.2005.033506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937070">Wei et al. (2006)</a> identified 14 mutations in the FH gene, including 9 novel mutations, in affected members of 13 families with HLRCC and 8 families with multiple cutaneous and uterine leiomyomata. Four unrelated families had the R58X mutation (<a href="#0003">136850.0003</a>) and 5 unrelated families had the R190H mutation (<a href="#0007">136850.0007</a>). Cutaneous leiomyomata were present in 16 (76%) of 21 families, ranging from mild to severe. All 22 female mutation carriers from 16 families had uterine fibroids. Renal tumors occurred in 13 (62%) of 21 families. No genotype/phenotype correlations were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To examine the cancer risk and tumor spectrum in Finnish families positive for FH mutations, <a href="#21" class="mim-tip-reference" title="Lehtonen, H. J., Kiuru, M., Ylisaukko-oja, S. K., Salovaara, R., Herva, R., Koivisto, P. A., Vierimaa, O., Aittomaki, K., Pukkala, E., Launonen, V., Aaltonen, L. A. <strong>Increased risk of cancer in patients with fumarate hydratase germline mutation.</strong> J. Med. Genet. 43: 523-526, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155190[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/10.1136/jmg.2005.036400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155190">Lehtonen et al. (2006)</a> collected genealogic and cancer data from 868 individuals. FH mutation status was analyzed in all 98 available patients. The standardized incidence ratio (SIR) was 6.5 for renal cell carcinoma (RCC) and 71 for uterine leiomyosarcoma (ULMS). The overall cancer risk was statistically significantly increased in the age group of 15 to 29 years, consistent with features of cancer predisposition families in general. An FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, <a href="#21" class="mim-tip-reference" title="Lehtonen, H. J., Kiuru, M., Ylisaukko-oja, S. K., Salovaara, R., Herva, R., Koivisto, P. A., Vierimaa, O., Aittomaki, K., Pukkala, E., Launonen, V., Aaltonen, L. A. <strong>Increased risk of cancer in patients with fumarate hydratase germline mutation.</strong> J. Med. Genet. 43: 523-526, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155190[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/10.1136/jmg.2005.036400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155190">Lehtonen et al. (2006)</a> observed several benign tumors including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16155190" 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>As part of the French National Cancer Institute study, <a href="#15" class="mim-tip-reference" title="Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others. <strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong> J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21398687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21398687</a>] [<a href="https://doi.org/10.1136/jmg.2010.085068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21398687">Gardie et al. (2011)</a> identified 32 different heterozygous germline mutations in the FH gene, including 21 novel mutations, in 40 (71.4%) of 56 families with proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23 probands with isolated type 2 papillary renal cell carcinoma, including 2 patients with no family history. In vitro functional expression studies showed that all mutations caused about a 50% decrease in FH enzymatic activity. In addition, there were 5 asymptomatic mutation carriers in 3 families, indicating incomplete penetrance. The findings indicated that renal call carcinoma can be the only manifestation of this disorder. No genotype/phenotype correlations were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21398687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>15 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=136850[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a patient of Arab ancestry with fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>), <a href="#8" class="mim-tip-reference" title="Coughlin, E. M., Chalmers, R. A., Slaugenhaupt, S. A., Gusella, J. F., Shih, V. E., Ramesh, V. <strong>Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993."None>Coughlin et al. (1993)</a> identified a G-to-A transition at nucleotide 793 of the FH gene, resulting in an ala265-to-thr (A265T) substitution. The father was shown to be heterozygous for the mutation.</p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017618 OR RCV002426509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017618, RCV002426509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017618...</a>
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<p>Bourgeron et al. (<a href="#4" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Rotig, A., Munnich, A., Landrieu, P., Rustin, P. <strong>Molecular characterization of fumarase deficiency in two children with progressive encephalopathy. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A891 only, 1993."None>1993</a>, <a href="#3" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P. <strong>Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.</strong> J. Clin. Invest. 93: 2514-2518, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8200987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8200987</a>] [<a href="https://doi.org/10.1172/JCI117261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8200987">1994</a>) described a glu319-to-gln (E319Q) mutation in the FH gene in 2 daughters of first-cousin Moroccan parents who presented with progressive encephalopathy, dystonia, leukopenia, and neutropenia at an early age. Elevation of lactate in the cerebrospinal fluid (so-called hyperlactatorachia) and high fumarate excretion in the urine led <a href="#3" class="mim-tip-reference" title="Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P. <strong>Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.</strong> J. Clin. Invest. 93: 2514-2518, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8200987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8200987</a>] [<a href="https://doi.org/10.1172/JCI117261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8200987">Bourgeron et al. (1994)</a> to investigate the activities of the respiratory chain and of the Krebs cycle, and finally to identify fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>). The deficiency was profound, was present in all tissues investigated, and affected the cytosolic and mitochondrial isoenzymes to the same degree. The sibs were homozygous for a missense mutation, a G-to-C transversion at nucleotide 955. The predicted amino acid substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8200987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017619 OR RCV000130873 OR RCV000199330 OR RCV000515176" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017619, RCV000130873, RCV000199330, RCV000515176" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017619...</a>
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<p>In 3 families, <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> found that members affected by multiple cutaneous and uterine leiomyomata (HLRCC; <a href="/entry/150800">150800</a>) had a change at codon 58 from CGA (arg) to TGA (stop) (R58X) in exon 2 of the FH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated families with hereditary leiomyomatosis and renal cell cancer, <a href="#34" class="mim-tip-reference" title="Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R. <strong>Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.</strong> J. Med. Genet. 43: 18-27, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937070[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/10.1136/jmg.2005.033506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937070">Wei et al. (2006)</a> identified the R58X mutation, resulting from a 172C-T transition. The R58X mutation was also identified in affected members of a fourth unrelated family with multiple cutaneous and uterine leiomyomata. Haplotype analysis of the families did not show a founder effect, suggesting that R58X represents a hotspot mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913121 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913121;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017620 OR RCV000078148 OR RCV000493777 OR RCV005016360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017620, RCV000078148, RCV000493777, RCV005016360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017620...</a>
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<p>In 6 separate families, <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> found that individuals with multiple cutaneous and uterine leiomyomata (HLRCC; <a href="/entry/150800">150800</a>) were heterozygous for a mutation in codon 64 in exon 2 of the FH gene converting AAC (asn) to ACC (thr) (N64T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" 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 55-year-old man with hereditary leiomyomatosis and renal cell cancer and the N64T mutation in the FH gene, <a href="#6" class="mim-tip-reference" title="Carvajal-Carmona, L. G., Alam, N. A., Pollard, P. J., Jones, A. M., Barclay, E., Wortham, N., Pignatelli, M., Freeman, A., Pomplun, S., Ellis, I., Poulsom, R., El-Bahrawy, M. A., Berney, D. M., Tomlinson, I. P. M. <strong>Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations.</strong> J. Clin. Endocr. Metab. 91: 3071-3075, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16757530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16757530</a>] [<a href="https://doi.org/10.1210/jc.2006-0183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16757530">Carvajal-Carmona et al. (2006)</a> identified a Leydig cell tumor of the testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16757530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs780001199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs780001199;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs780001199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs780001199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017621 OR RCV002513083" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017621, RCV002513083" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017621...</a>
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<p>In 2 Finnish families with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC; <a href="/entry/150800">150800</a>), <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> found a 2-bp deletion in codon 181 in exon 4 of the FH gene: conversion of GAGTTT to GTTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913122;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913122?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017622 OR RCV000130875 OR RCV000197989 OR RCV003466863 OR RCV005007862" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017622, RCV000130875, RCV000197989, RCV003466863, RCV005007862" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017622...</a>
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<p>In a Finnish family with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC; <a href="/entry/150800">150800</a>), <a href="#30" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> found a nonsense mutation converting codon 300 in exon 6 of the FH gene from CGA (arg) to TGA (stop) (R300X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017623 OR RCV000178717 OR RCV000196988 OR RCV000493379 OR RCV003128387 OR RCV003330393 OR RCV004541007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017623, RCV000178717, RCV000196988, RCV000493379, RCV003128387, RCV003330393, RCV004541007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017623...</a>
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<p>In 4 individuals from a family with cutaneous and uterine leiomyomatosis and renal cell cancer (HLRCC; <a href="/entry/150800">150800</a>), <a href="#31" class="mim-tip-reference" title="Toro, J. R., Nickerson, M. L., Wei, M.-H., Warren, M. B., Glenn, G. M., Turner, M. L., Stewart, L., Duray, P., Tourre, O., Sharma, N., Choyke, P., Stratton, P., Merino, M., Walther, M. M., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.</strong> Am. J. Hum. Genet. 73: 95-106, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12772087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12772087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12772087[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/10.1086/376435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12772087">Toro et al. (2003)</a> identified a 569G-A transition in exon 4 of the FH gene, resulting in an arg190-to-his (R190H) mutation. The R190H mutation was also present in 10 other unrelated families with cutaneous and uterine leiomyomatosis, but screening for occult renal tumors in affected individuals from these 10 families did not identify renal tumors. Thus there appeared to be other genetic and/or environmental factors that influenced the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12772087" 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="#34" class="mim-tip-reference" title="Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R. <strong>Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.</strong> J. Med. Genet. 43: 18-27, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937070[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/10.1136/jmg.2005.033506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937070">Wei et al. (2006)</a> identified the R190H mutation in affected members of 3 unrelated families with HLRCC. The R190H mutation was also identified in affected members of 2 additional families with multiple cutaneous and uterine leiomyomata. A founder effect could not be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913123;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913123?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017624 OR RCV001781272 OR RCV002362588" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017624, RCV001781272, RCV002362588" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017624...</a>
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<p><a href="#31" class="mim-tip-reference" title="Toro, J. R., Nickerson, M. L., Wei, M.-H., Warren, M. B., Glenn, G. M., Turner, M. L., Stewart, L., Duray, P., Tourre, O., Sharma, N., Choyke, P., Stratton, P., Merino, M., Walther, M. M., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.</strong> Am. J. Hum. Genet. 73: 95-106, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12772087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12772087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12772087[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/10.1086/376435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12772087">Toro et al. (2003)</a> described a family with leiomyomatosis and renal cell cancer (HLRCC; <a href="/entry/150800">150800</a>) associated with a 569G-T transversion in exon 4 of the FH gene, resulting in an arg190-to-leu (R190L) mutation. The nucleotide substitution occurred at the same position as that changed in the common R190H mutation (<a href="#0007">136850.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12772087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75086406 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75086406;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75086406?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75086406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75086406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017625 OR RCV000489422 OR RCV002433458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017625, RCV000489422, RCV002433458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017625...</a>
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<p>In affected members of a family with multiple cutaneous and uterine leiomyomata (HLRCC: <a href="/entry/150800">150800</a>), <a href="#7" class="mim-tip-reference" title="Chan, I., Wong, T., Martinez-Mir, A., Christiano, A. M., McGrath, J. A. <strong>Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.</strong> Clin. Exp. Derm. 30: 75-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15663510</a>] [<a href="https://doi.org/10.1111/j.1365-2230.2004.01675.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15663510">Chan et al. (2005)</a> identified a heterozygous 173G-C transversion in exon 3 of the FH gene, resulting in an arg58-to-pro (R58P) substitution. The proband was a 77-year-old Polish woman with multiple cutaneous leiomyomas and uterine fibroids. Her eldest daughter had a similar phenotype, and 2 unaffected daughters did not have the mutation. Her son had multiple skin leiomyomas and was diagnosed with metastatic papillary renal cell cancer at age 50 years, and his asymptomatic 20-year-old son was also found to carry the mutation and was thus likely to develop skin leiomyomas, but the risk of renal cancer was difficult to predict. <a href="#7" class="mim-tip-reference" title="Chan, I., Wong, T., Martinez-Mir, A., Christiano, A. M., McGrath, J. A. <strong>Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.</strong> Clin. Exp. Derm. 30: 75-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15663510</a>] [<a href="https://doi.org/10.1111/j.1365-2230.2004.01675.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15663510">Chan et al. (2005)</a> noted that a nonsense mutation in the same residue had been reported (R58X; <a href="#0003">136850.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Heinritz, W., Paasch, U., Sticherling, M., Wittekind, C., Simon, J. C., Froster, U. G., Renner, R. <strong>Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC).</strong> Ann. Hum. Genet. 72: 35-40, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17908262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17908262</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2007.00396.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17908262">Heinritz et al. (2008)</a> identified the R58P mutation in affected members of a large German family with multiple cutaneous and uterine leiomyomata without renal cancer. Family history revealed that this German family originally came from Poland but was dispersed after World War II. Haplotype analysis of this family and that reported by <a href="#7" class="mim-tip-reference" title="Chan, I., Wong, T., Martinez-Mir, A., Christiano, A. M., McGrath, J. A. <strong>Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.</strong> Clin. Exp. Derm. 30: 75-78, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15663510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15663510</a>] [<a href="https://doi.org/10.1111/j.1365-2230.2004.01675.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15663510">Chan et al. (2005)</a> demonstrated a founder effect for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17908262+15663510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022554 OR RCV000078149 OR RCV000492836 OR RCV003335052 OR RCV003483435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022554, RCV000078149, RCV000492836, RCV003335052, RCV003483435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022554...</a>
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<p>In 2 brothers with infantile-lethal fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>), <a href="#22" class="mim-tip-reference" title="Mroch, A. R., Laudenschlager, M., Flanagan, J. D. <strong>Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency.</strong> Am. J. Med. Genet. 158A: 155-158, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22069215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22069215</a>] [<a href="https://doi.org/10.1002/ajmg.a.34344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22069215">Mroch et al. (2012)</a> identified compound heterozygosity for a 521C-G transversion in the FH gene, resulting in a pro174-to-arg (P174R) substitution, and a whole gene deletion (<a href="#0011">136850.0011</a>). The older sib was born prematurely and showed hypotonia and respiratory insufficiency after birth. Both sibs had structural brain malformations, including ventriculomegaly and agenesis of the corpus callosum, detected by prenatal ultrasound. Both also had hepatic involvement, with cholestasis, variable iron deposition, fibrosis, and liver failure. Electron microscopy of the liver revealed multiple swollen mitochondria with flat, plate-like, haphazardly arranged cristae. Biochemical studies showed increased urinary tyrosine metabolites, citric cycle intermediates, citrulline, fumaric, malic, and succinic acids, and skin biopsy showed fumarase deficiency. Postmortem examination showed a distended abdomen, and the liver showed intrahepatic bile stasis. Both patients died at about 3 weeks of age. The second sib was diagnosed prenatally by molecular testing of amniocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22069215" 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>For discussion of the deletion in the FH gene that was found in compound heterozygous state in patients with fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>) by <a href="#22" class="mim-tip-reference" title="Mroch, A. R., Laudenschlager, M., Flanagan, J. D. <strong>Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency.</strong> Am. J. Med. Genet. 158A: 155-158, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22069215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22069215</a>] [<a href="https://doi.org/10.1002/ajmg.a.34344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22069215">Mroch et al. (2012)</a>, see <a href="#0010">136850.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22069215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs367543046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs367543046;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs367543046?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs367543046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs367543046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000034483 OR RCV000034921 OR RCV000164180 OR RCV001000649 OR RCV001762110 OR RCV004555534 OR RCV005007937" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000034483, RCV000034921, RCV000164180, RCV001000649, RCV001762110, RCV004555534, RCV005007937" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000034483...</a>
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<p>In 2 sibs of French/UK ancestry with an attenuated form of fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>), <a href="#27" class="mim-tip-reference" title="Prasad, C., Napier, M. P., Rupar, C. A., Prasad, C. <strong>Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer.</strong> Clin. Dysmorph. 26: 117-120, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27541980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27541980</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27541980">Prasad et al. (2017)</a> identified compound heterozygosity for 2 mutations in the FH gene: a maternally inherited 3-bp duplication (c.1431_1433dupAAA), resulting in a duplication of lysine at amino acid 477 (K477dup), and a paternally inherited splice site mutation (c.1390+1G-T) in intron 9 (<a href="#0013">136850.0013</a>). The mutations were identified by exome sequencing. An unaffected younger brother was found to be a carrier of the paternal mutation. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27541980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 FUMARASE DEFICIENCY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039367;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886039367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs886039367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000255853 OR RCV001011336 OR RCV001251427 OR RCV003454775" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000255853, RCV001011336, RCV001251427, RCV003454775" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000255853...</a>
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<p>For discussion of the splice site mutation (c.1390+1G-T) in intron 9 of the FH gene that was found in compound heterozygous state in 2 sibs with an attenuated form of fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>) by <a href="#27" class="mim-tip-reference" title="Prasad, C., Napier, M. P., Rupar, C. A., Prasad, C. <strong>Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer.</strong> Clin. Dysmorph. 26: 117-120, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27541980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27541980</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27541980">Prasad et al. (2017)</a>, see <a href="#0012">136850.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27541980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs145116688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs145116688;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs145116688?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs145116688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs145116688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000197441 OR RCV000456662 OR RCV001013787 OR RCV005016554" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000197441, RCV000456662, RCV001013787, RCV005016554" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000197441...</a>
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<p>In a patient with fumarate hydratase deficiency (FMRD; <a href="/entry/606812">606812</a>), <a href="#16" class="mim-tip-reference" title="Grocott, O., Phanor, S. K., Fung, F., Thibert, R. L., Berkmen, M. B. <strong>Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.</strong> Am. J. Med. Genet. 182A: 504-507, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31746132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31746132</a>] [<a href="https://doi.org/10.1002/ajmg.a.61415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31746132">Grocott et al. (2020)</a> identified compound heterozygous mutations in the FH gene: a c.94A-G transition in exon 2, resulting in an asp65-to-gly (D65G) substitution, and a 1-bp deletion (c.1293delA; <a href="#0015">136850.0015</a>) in exon 9, resulting in a frameshift and premature termination (Glu432LysfsTer17). The mutations were identified by sequencing of the FH gene and the parents were found to be mutation carriers. Urine organic acids in the patient demonstrated elevated fumaric acid, and cytosolic and mitochondrial fumarase enzyme activities were decreased in patient fibroblasts. Fumarase enzyme was purified from plasmids containing FH with each of the patient's mutations. Fumarase with the c.1293delA mutation had defective enzyme activity and oligomerization. Fumarase with the D65G mutation had a lower catalytic activity compared to wildtype. The patient's father, who carried the c.1293delA mutation, had a history of renal cell cancer, and her mother, who carried the D65G mutation, had a history of uterine leiomyomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31746132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 FUMARASE DEFICIENCY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs398123163 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123163;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs398123163?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398123163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398123163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000078145 OR RCV000445588 OR RCV000461548 OR RCV000493624" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000078145, RCV000445588, RCV000461548, RCV000493624" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000078145...</a>
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<p>For discussion of the 1-bp deletion (c.1293delA) in exon 9 of the FH gene, resulting in a frameshift and premature termination (Glu432LysfsTer17), that was identified in compound heterozygous state in a patient with fumarate hydratase deficiency (FMRD; <a href="/entry/606812">606812</a>) by <a href="#16" class="mim-tip-reference" title="Grocott, O., Phanor, S. K., Fung, F., Thibert, R. L., Berkmen, M. B. <strong>Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.</strong> Am. J. Med. Genet. 182A: 504-507, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31746132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31746132</a>] [<a href="https://doi.org/10.1002/ajmg.a.61415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31746132">Grocott et al. (2020)</a>, see <a href="#0014">136850.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31746132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Busby1976" class="mim-tip-reference" title="Busby, N., Courval, J., Francke, U. <strong>Regional assignments of the genes for fumarate hydratase and guanylate kinase on chromosome 1 and for lysosomal acid phosphatase and esterase A4 on chromosome 11.</strong> Cytogenet. Cell Genet. 16: 105-107, 1976.">Busby et al. (1976)</a>; <a href="#Edwards1979" class="mim-tip-reference" title="Edwards, Y. H., Hopkinson, D. A. <strong>The genetic determination of fumarase isozymes in human tissues.</strong> Ann. Hum. Genet. 42: 303-313, 1979.">Edwards and Hopkinson (1979)</a>; <a href="#Petrova-Benedict1987" class="mim-tip-reference" title="Petrova-Benedict, R., Robinson, B. H., Stacey, T. E., Mistry, J., Chalmers, R. A. <strong>Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing.</strong> Am. J. Hum. Genet. 40: 257-266, 1987.">Petrova-Benedict
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et al. (1987)</a>; <a href="#Tolley1975" class="mim-tip-reference" title="Tolley, E., Craig, I. <strong>Presence of two forms of fumarase (fumarate hydratase EC 4.2.1.2) in mammalian cells: immunological characterisation and genetic analysis in somatic cell hybrids; confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1.</strong> Biochem. Genet. 13: 867-883, 1975.">Tolley and Craig (1975)</a>; <a href="#van1974" class="mim-tip-reference" title="van Someren, H., Beyersbergen van Henegouwen, H., de Wit, J. <strong>Evidence for synteny between the human loci for fumarate hydratase, UDG glucose pyrophosphorylase, 6-phosphogluconate dehydrogenase, phosphoglucomutase-1, and peptidase-C in man-Chinese hamster somatic cell hybrids.</strong> Cytogenet. Cell Genet. 13: 150-152, 1974.">van Someren et al. (1974)</a>
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[<a href="https://doi.org/10.1093/hmg/ddg148" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI117261" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000130565" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-0183" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2230.2004.01675.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000130569" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2010.085068" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01116247" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201326" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.036400" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.34344" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0167-4838(85)90080-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi227" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/MCD.0000000000000148" target="_blank">Full Text</a>]
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<strong>Presence of two forms of fumarase (fumarate hydratase EC 4.2.1.2) in mammalian cells: immunological characterisation and genetic analysis in somatic cell hybrids; confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1.</strong>
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[<a href="https://doi.org/10.1007/BF00484417" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng849" target="_blank">Full Text</a>]
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<strong>Evidence for synteny between the human loci for fumarate hydratase, UDG glucose pyrophosphorylase, 6-phosphogluconate dehydrogenase, phosphoglucomutase-1, and peptidase-C in man-Chinese hamster somatic cell hybrids.</strong>
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[<a href="https://doi.org/10.1159/000130273" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.033506" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 11/18/2022
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Hilary J. Vernon - updated : 08/06/2020<br>Patricia A. Hartz - updated : 8/3/2012<br>Cassandra L. Kniffin - updated : 2/16/2012<br>Ada Hamosh - updated : 9/21/2011<br>George E. Tiller - updated : 11/21/2008<br>Cassandra L. Kniffin - updated : 10/6/2008<br>John A. Phillips, III - updated : 6/21/2007<br>Victor A. McKusick - updated : 7/5/2006<br>Cassandra L. Kniffin - updated : 2/13/2006<br>Victor A. McKusick - updated : 4/26/2005<br>George E. Tiller - updated : 3/9/2005<br>Victor A. McKusick - updated : 12/20/2004<br>Victor A. McKusick - updated : 6/25/2003<br>Victor A. McKusick - updated : 10/23/2002<br>Cassandra L. Kniffin - reorganized : 4/4/2002<br>Victor A. McKusick - updated : 2/28/2002
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Victor A. McKusick : 6/4/1986
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carol : 04/19/2023
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carol : 11/21/2022<br>carol : 11/18/2022<br>carol : 03/25/2022<br>carol : 08/07/2020<br>carol : 08/06/2020<br>alopez : 08/09/2016<br>carol : 03/12/2015<br>mcolton : 2/5/2015<br>carol : 9/18/2013<br>carol : 3/25/2013<br>carol : 8/15/2012<br>terry : 8/3/2012<br>carol : 2/21/2012<br>ckniffin : 2/16/2012<br>alopez : 9/22/2011<br>terry : 9/21/2011<br>ckniffin : 9/13/2011<br>wwang : 8/16/2011<br>ckniffin : 8/11/2011<br>wwang : 11/21/2008<br>wwang : 10/16/2008<br>ckniffin : 10/6/2008<br>carol : 6/21/2007<br>alopez : 7/7/2006<br>terry : 7/5/2006<br>wwang : 2/28/2006<br>ckniffin : 2/13/2006<br>tkritzer : 4/29/2005<br>terry : 4/26/2005<br>alopez : 3/9/2005<br>alopez : 3/9/2005<br>tkritzer : 1/10/2005<br>terry : 12/20/2004<br>tkritzer : 7/17/2003<br>tkritzer : 7/11/2003<br>terry : 6/25/2003<br>alopez : 10/24/2002<br>terry : 10/23/2002<br>alopez : 4/12/2002<br>ckniffin : 4/4/2002<br>ckniffin : 4/4/2002<br>carol : 4/4/2002<br>ckniffin : 4/4/2002<br>ckniffin : 4/4/2002<br>terry : 3/27/2002<br>alopez : 3/1/2002<br>terry : 2/28/2002<br>terry : 7/24/1998<br>jason : 6/15/1994<br>terry : 4/27/1994<br>carol : 10/28/1993<br>carol : 10/18/1993<br>supermim : 3/16/1992<br>carol : 11/20/1990
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<strong>*</strong> 136850
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<h3>
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FUMARATE HYDRATASE; FH
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<em>Alternative titles; symbols</em>
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FUMARASE
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Other entities represented in this entry:
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FUMARATE HYDRATASE, CYTOSOLIC, INCLUDED; FH1, INCLUDED
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<span class="h4 mim-font">
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FUMARATE HYDRATASE, MITOCHONDRIAL, INCLUDED; FH2, INCLUDED
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<strong><em>HGNC Approved Gene Symbol: FH</em></strong>
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<strong>SNOMEDCT:</strong> 1162799008, 237983002;
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Cytogenetic location: 1q43
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:241,497,603-241,519,755 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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1q43
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Fumarase deficiency
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606812
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Autosomal recessive
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3
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Leiomyomatosis and renal cell cancer
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150800
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Fumarate hydratase, or fumarase (EC 4.2.1.2), is an enzymatic component of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion of fumarate to malate.</p>
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<strong>Cloning and Expression</strong>
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<p>Edwards and Hopkinson (1979) studied a family with an electrophoretic variant of FH. Two persons had variation in both the soluble and the mitochondrial forms, suggesting that they are determined by a single locus. Doonan et al. (1984) cited evidence suggesting that the isoenzymes of fumarase are translated in precursor form from 2 different mRNA molecules, these mRNAs in turn arising from alternative splicing of a single gene transcript. </p><p>Using peptide mapping, O'Hare and Doonan (1985) showed that the cytosolic and mitochondrial fumarases from pig liver are identical over nearly all of their amino acid sequences, but that they differ at their N termini. </p><p>Kinsella and Doonan (1986) cloned human fumarase from a liver cDNA library. The deduced 468-amino acid protein, with the exception of an N-terminal methionine, appeared to be the mitochondrial form. Kinsella and Doonan (1986) found an unusually high degree of identity of structure between human fumarase and that from B. subtilis and E. coli. </p><p>Suzuki et al. (1989) cloned rat liver fumarase, which encodes a deduced 507-amino acid protein with a 41-amino acid prosequence. Comparison of mature peptide sequences of mitochondrial and cytosolic fumarases revealed identity, with the exception that the N-terminal alanine of cytosolic fumarase was acetylated. Northern blot analysis of rat liver showed a single mRNA species of about 1.8 kb. Suzuki et al. (1989) concluded that the mitochondrial and cytosolic forms of fumarase are encoded by a single transcript and that posttranslational processing directs its cellular localization. </p><p>By immunohistochemical analysis, Bourgeron et al. (1994) found that fumarase localized to the mitochondrion, but not cytosol, in normal human brain, consistent with the findings in rat. </p>
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<strong>Mapping</strong>
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<p>Van Someren et al. (1974) and Craig et al. (1976) found that the fumarase locus is on chromosome 1, possibly in the area 1q42. Despoisses et al. (1984) narrowed the regional assignment of FH to 1q42.1 by gene dosage studies in patients with various types of partial trisomy or partial monosomy of 1q. Coughlin et al. (1993) mapped the FH gene to chromosome 1 using PCR-amplified cDNA as a probe in Southern blots of genomic DNA from a series of mouse/human somatic cell hybrids. They observed related sequences on chromosomes 13 and 5. </p>
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<strong>Gene Function</strong>
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<p>Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase and succinate dehydrogenases (see, e.g., SDHB 185470) act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer and to paragangliomas (see 115310), respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paragangliomas and leiomyoma and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300). </p><p>Using Fh -/- mouse embryonic fibroblasts and FH-deficient papillary renal carcinoma tissues, O'Flaherty et al. (2010) showed that deficiency in cytosolic fumarase directly led to HIF1-alpha activation. As expected, Fh -/- mouse cells showed elevated fumarate accumulation and lactate production, and reduced cellular respiration. Fh -/- also showed upregulated Hif1-alpha transcriptional activity due to reduced Hif1-alpha prolyl hydroxylation. Profound dysregulation of HIF1-alpha also occurred in FH-associated neoplasias. Reintroduction of wildtype human FH lacking the mitochondrial targeting sequence largely ablated fumarate accumulation and restored HIF1-alpha prolyl hydroxylation and inactivation without restoration of mitochondrial respiration. O'Flaherty et al. (2010) proposed that fumarate is a catalytic inhibitor of HIF1-alpha prolyl hydroxylation, and that fumarase deficiency may mimic hypoxia, resulting in HIF1-alpha activation. </p><p>Using genetically modified mouse kidney cells in which Fh1 had been deleted, Frezza et al. (2011) applied a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of heme, enables Fh1-deficient cells to use accumulated tricarboxylic acid (TCA) cycle metabolites and permits partial mitochondrial NADH production. Frezza et al. (2011) predicted and confirmed that targeting this pathway would render Fh1-deficient cells nonviable, while sparing wildtype Fh1-containing cells. Frezza et al. (2011) concluded that their work went beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of heme oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a potential target for treating HLRCC (150800) patients. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Fumarase Deficiency</em></strong></p><p>
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In patients with fumarase deficiency (FMRD; 606812), Bourgeron et al. (1993, 1994) and Coughlin et al. (1993) identified mutations in the FH gene (136850.0001 and 136850.0002). </p><p>In 2 sisters with an attenuated form of FMRD, Prasad et al. (2017) identified compound heterozygous mutations in the FH gene: a duplication (K477dup; 136850.0012) and a splice site mutation (136850.0013). The sibs had no encephalopathy and near-normal urine fumaric acid levels. The mutations segregated with the disorder in the family. </p><p>In a patient with FMRD, Grocott et al. (2020) identified compound heterozygous mutations in the FH gene (D65G, 136850.0014; c.1293delA, 136850.0015). Fumarase enzyme was purified from plasmids containing FH with each of the patient's mutations. Fumarase with the c.1293delA mutation had defective enzyme activity and oligomerization. Fumarase with the D65G mutation had a lower catalytic activity compared to wildtype. Urine organic acids in the patient demonstrated elevated fumaric acid, and cytosolic and mitochondrial fumarase enzyme activities were decreased in patient fibroblasts. The patient had seizures, hypotonia, and developmental delay but survived until 16 years of age. </p><p><strong><em>Hereditary Leiomyomatosis and Renal Cell Cancer</em></strong></p><p>
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In patients with hereditary leiomyomatosis and renal cell cancer (HRLCC; 150800), Tomlinson et al. (2002) identified several heterozygous mutations in the FH gene (136850.0005 and 136850.0006). </p><p>In patients with multiple cutaneous and uterine leiomyomata, Tomlinson et al. (2002) identified heterozygous mutations in the FH gene (136850.0003 and 136850.0004). </p><p>Using sequence analysis, Toro et al. (2003) identified germline mutations in the FH gene in 31 of 35 (89%) families with cutaneous leiomyomas. Eighteen of the 20 different mutations they identified-- 2 insertions, 5 small deletions that caused frameshifts leading to premature termination of the protein, and 13 missense--were novel. The same mutation, arg190 to his (R190H; 136850.0007), was identified in 11 unrelated families. Cutaneous leiomyomas were found in 81 individuals (47 women and 34 men). Uterine leiomyomas were also found in 98% (46 of 47) of women with cutaneous leiomyomas. Total hysterectomy was performed in 89% (41 of 46) of women with cutaneous and uterine leiomyomas, 44% before or at age 30 years. In 13 individuals in 5 families, Toro et al. (2003) identified unilateral and solitary renal tumors. Papillary type II renal cell carcinoma was present in 7 individuals from 4 families, and another individual from 1 of these families had collecting duct carcinoma of the kidney. The study expanded the histologic spectrum of renal tumors and FH mutations associated with hereditary leiomyomatosis and renal cell carcinoma. </p><p>Barker et al. (2002) analyzed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harbored somatic mutations in fumarate hydratase. Only 5% (7 of 129) of the leiomyomas showed allele imbalance at 1q42-q43, and no somatic mutations in fumarate hydratase were observed. </p><p>Alam et al. (2003) reported 20 FH mutations in 35 of 46 probands with multiple cutaneous and uterine leiomyomata (MCUL) or FH deficiency. Disease-associated missense FH changes mapped to highly conserved residues, mostly in or around the enzyme's active site or activation site. The mutation spectra in FH deficiency and MCUL were similar, although in the latter mutations tended to occur more 5-prime in the gene and were predicted to result in a truncated or absent protein. The authors reported that not all mutation-carrier parents of FH deficiency children had a strong predisposition to leiomyomata. Renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome; these cancers may have either type II papillary or collecting duct morphology. There was no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients may indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. The authors concluded that MCUL is probably a genetically homogeneous tumor predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity. </p><p>To determine whether FH mutations may predispose women to developing nonsyndromic uterine leiomyomas (UL; 150699), Gross et al. (2004) performed a genetic linkage study with DNA from 123 families containing at least 1 affected sister pair. In addition, to assess the frequency of FH loss specifically in uterine leiomyomas with 1q rearrangements, they performed a FISH analysis of UL. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (p = 0.04). FISH results showed that 1 copy of FH was absent in 9 of 11 ULs. Gross et al. (2004) concluded that loss of FH may be a significant event in the pathogenesis of a subset of nonsyndromic ULs. </p><p>Because some individuals with HLRCC with a germline FH mutation have breast cancer (114480), Kiuru et al. (2005) analyzed germline FH mutations from 85 Finnish breast cancer patients, most of whom were selected based on positive family or personal history for malignancies associated with HLRCC. No mutations were found. Kiuru et al. (2005) concluded that FH is not a major predisposing gene for familial breast cancer. </p><p>Wei et al. (2006) identified 14 mutations in the FH gene, including 9 novel mutations, in affected members of 13 families with HLRCC and 8 families with multiple cutaneous and uterine leiomyomata. Four unrelated families had the R58X mutation (136850.0003) and 5 unrelated families had the R190H mutation (136850.0007). Cutaneous leiomyomata were present in 16 (76%) of 21 families, ranging from mild to severe. All 22 female mutation carriers from 16 families had uterine fibroids. Renal tumors occurred in 13 (62%) of 21 families. No genotype/phenotype correlations were identified. </p><p>To examine the cancer risk and tumor spectrum in Finnish families positive for FH mutations, Lehtonen et al. (2006) collected genealogic and cancer data from 868 individuals. FH mutation status was analyzed in all 98 available patients. The standardized incidence ratio (SIR) was 6.5 for renal cell carcinoma (RCC) and 71 for uterine leiomyosarcoma (ULMS). The overall cancer risk was statistically significantly increased in the age group of 15 to 29 years, consistent with features of cancer predisposition families in general. An FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, Lehtonen et al. (2006) observed several benign tumors including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas. </p><p>As part of the French National Cancer Institute study, Gardie et al. (2011) identified 32 different heterozygous germline mutations in the FH gene, including 21 novel mutations, in 40 (71.4%) of 56 families with proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23 probands with isolated type 2 papillary renal cell carcinoma, including 2 patients with no family history. In vitro functional expression studies showed that all mutations caused about a 50% decrease in FH enzymatic activity. In addition, there were 5 asymptomatic mutation carriers in 3 families, indicating incomplete penetrance. The findings indicated that renal call carcinoma can be the only manifestation of this disorder. No genotype/phenotype correlations were identified. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 FUMARASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ALA265THR
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<br />
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SNP: rs387906545,
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ClinVar: RCV000017617
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<p>In a patient of Arab ancestry with fumarase deficiency (FMRD; 606812), Coughlin et al. (1993) identified a G-to-A transition at nucleotide 793 of the FH gene, resulting in an ala265-to-thr (A265T) substitution. The father was shown to be heterozygous for the mutation.</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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<strong>.0002 FUMARASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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FH, GLU319GLN
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<br />
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SNP: rs121913119,
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ClinVar: RCV000017618, RCV002426509
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</div>
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<span class="mim-text-font">
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<p>Bourgeron et al. (1993, 1994) described a glu319-to-gln (E319Q) mutation in the FH gene in 2 daughters of first-cousin Moroccan parents who presented with progressive encephalopathy, dystonia, leukopenia, and neutropenia at an early age. Elevation of lactate in the cerebrospinal fluid (so-called hyperlactatorachia) and high fumarate excretion in the urine led Bourgeron et al. (1994) to investigate the activities of the respiratory chain and of the Krebs cycle, and finally to identify fumarase deficiency (FMRD; 606812). The deficiency was profound, was present in all tissues investigated, and affected the cytosolic and mitochondrial isoenzymes to the same degree. The sibs were homozygous for a missense mutation, a G-to-C transversion at nucleotide 955. The predicted amino acid substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for the mutation. </p>
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</span>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ARG58TER
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<br />
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SNP: rs121913120,
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ClinVar: RCV000017619, RCV000130873, RCV000199330, RCV000515176
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</span>
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<span class="mim-text-font">
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<p>In 3 families, Tomlinson et al. (2002) found that members affected by multiple cutaneous and uterine leiomyomata (HLRCC; 150800) had a change at codon 58 from CGA (arg) to TGA (stop) (R58X) in exon 2 of the FH gene. </p><p>In 3 unrelated families with hereditary leiomyomatosis and renal cell cancer, Wei et al. (2006) identified the R58X mutation, resulting from a 172C-T transition. The R58X mutation was also identified in affected members of a fourth unrelated family with multiple cutaneous and uterine leiomyomata. Haplotype analysis of the families did not show a founder effect, suggesting that R58X represents a hotspot mutation. </p>
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</span>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ASN64THR
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<br />
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SNP: rs121913121,
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ClinVar: RCV000017620, RCV000078148, RCV000493777, RCV005016360
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 6 separate families, Tomlinson et al. (2002) found that individuals with multiple cutaneous and uterine leiomyomata (HLRCC; 150800) were heterozygous for a mutation in codon 64 in exon 2 of the FH gene converting AAC (asn) to ACC (thr) (N64T). </p><p>In a 55-year-old man with hereditary leiomyomatosis and renal cell cancer and the N64T mutation in the FH gene, Carvajal-Carmona et al. (2006) identified a Leydig cell tumor of the testis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, 2-BP DEL
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<br />
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SNP: rs780001199,
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ClinVar: RCV000017621, RCV002513083
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Finnish families with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC; 150800), Tomlinson et al. (2002) found a 2-bp deletion in codon 181 in exon 4 of the FH gene: conversion of GAGTTT to GTTT. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ARG300TER
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<br />
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SNP: rs121913122,
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gnomAD: rs121913122,
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ClinVar: RCV000017622, RCV000130875, RCV000197989, RCV003466863, RCV005007862
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Finnish family with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC; 150800), Tomlinson et al. (2002) found a nonsense mutation converting codon 300 in exon 6 of the FH gene from CGA (arg) to TGA (stop) (R300X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ARG190HIS
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<br />
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SNP: rs121913123,
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gnomAD: rs121913123,
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ClinVar: RCV000017623, RCV000178717, RCV000196988, RCV000493379, RCV003128387, RCV003330393, RCV004541007
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 individuals from a family with cutaneous and uterine leiomyomatosis and renal cell cancer (HLRCC; 150800), Toro et al. (2003) identified a 569G-A transition in exon 4 of the FH gene, resulting in an arg190-to-his (R190H) mutation. The R190H mutation was also present in 10 other unrelated families with cutaneous and uterine leiomyomatosis, but screening for occult renal tumors in affected individuals from these 10 families did not identify renal tumors. Thus there appeared to be other genetic and/or environmental factors that influenced the phenotype. </p><p>Wei et al. (2006) identified the R190H mutation in affected members of 3 unrelated families with HLRCC. The R190H mutation was also identified in affected members of 2 additional families with multiple cutaneous and uterine leiomyomata. A founder effect could not be determined. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ARG190LEU
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<br />
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SNP: rs121913123,
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gnomAD: rs121913123,
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ClinVar: RCV000017624, RCV001781272, RCV002362588
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Toro et al. (2003) described a family with leiomyomatosis and renal cell cancer (HLRCC; 150800) associated with a 569G-T transversion in exon 4 of the FH gene, resulting in an arg190-to-leu (R190L) mutation. The nucleotide substitution occurred at the same position as that changed in the common R190H mutation (136850.0007). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0009 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, ARG58PRO
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<br />
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SNP: rs75086406,
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gnomAD: rs75086406,
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ClinVar: RCV000017625, RCV000489422, RCV002433458
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with multiple cutaneous and uterine leiomyomata (HLRCC: 150800), Chan et al. (2005) identified a heterozygous 173G-C transversion in exon 3 of the FH gene, resulting in an arg58-to-pro (R58P) substitution. The proband was a 77-year-old Polish woman with multiple cutaneous leiomyomas and uterine fibroids. Her eldest daughter had a similar phenotype, and 2 unaffected daughters did not have the mutation. Her son had multiple skin leiomyomas and was diagnosed with metastatic papillary renal cell cancer at age 50 years, and his asymptomatic 20-year-old son was also found to carry the mutation and was thus likely to develop skin leiomyomas, but the risk of renal cancer was difficult to predict. Chan et al. (2005) noted that a nonsense mutation in the same residue had been reported (R58X; 136850.0003). </p><p>Heinritz et al. (2008) identified the R58P mutation in affected members of a large German family with multiple cutaneous and uterine leiomyomata without renal cancer. Family history revealed that this German family originally came from Poland but was dispersed after World War II. Haplotype analysis of this family and that reported by Chan et al. (2005) demonstrated a founder effect for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 FUMARASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, PRO174ARG
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<br />
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SNP: rs199822819,
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gnomAD: rs199822819,
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ClinVar: RCV000022554, RCV000078149, RCV000492836, RCV003335052, RCV003483435
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 brothers with infantile-lethal fumarase deficiency (FMRD; 606812), Mroch et al. (2012) identified compound heterozygosity for a 521C-G transversion in the FH gene, resulting in a pro174-to-arg (P174R) substitution, and a whole gene deletion (136850.0011). The older sib was born prematurely and showed hypotonia and respiratory insufficiency after birth. Both sibs had structural brain malformations, including ventriculomegaly and agenesis of the corpus callosum, detected by prenatal ultrasound. Both also had hepatic involvement, with cholestasis, variable iron deposition, fibrosis, and liver failure. Electron microscopy of the liver revealed multiple swollen mitochondria with flat, plate-like, haphazardly arranged cristae. Biochemical studies showed increased urinary tyrosine metabolites, citric cycle intermediates, citrulline, fumaric, malic, and succinic acids, and skin biopsy showed fumarase deficiency. Postmortem examination showed a distended abdomen, and the liver showed intrahepatic bile stasis. Both patients died at about 3 weeks of age. The second sib was diagnosed prenatally by molecular testing of amniocytes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 FUMARASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FH, DEL
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<br />
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ClinVar: RCV000022555
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the deletion in the FH gene that was found in compound heterozygous state in patients with fumarase deficiency (FMRD; 606812) by Mroch et al. (2012), see 136850.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0012 FUMARASE DEFICIENCY</strong>
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FH, 3-BP DUP, 1431AAA
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<br />
|
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|
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SNP: rs367543046,
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|
|
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gnomAD: rs367543046,
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|
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ClinVar: RCV000034483, RCV000034921, RCV000164180, RCV001000649, RCV001762110, RCV004555534, RCV005007937
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sibs of French/UK ancestry with an attenuated form of fumarase deficiency (FMRD; 606812), Prasad et al. (2017) identified compound heterozygosity for 2 mutations in the FH gene: a maternally inherited 3-bp duplication (c.1431_1433dupAAA), resulting in a duplication of lysine at amino acid 477 (K477dup), and a paternally inherited splice site mutation (c.1390+1G-T) in intron 9 (136850.0013). The mutations were identified by exome sequencing. An unaffected younger brother was found to be a carrier of the paternal mutation. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 FUMARASE DEFICIENCY</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FH, IVS9DS, G-T, +1
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<br />
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SNP: rs886039367,
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ClinVar: RCV000255853, RCV001011336, RCV001251427, RCV003454775
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|
</span>
|
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</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice site mutation (c.1390+1G-T) in intron 9 of the FH gene that was found in compound heterozygous state in 2 sibs with an attenuated form of fumarase deficiency (FMRD; 606812) by Prasad et al. (2017), see 136850.0012. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 FUMARASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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FH, ASP65GLY
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<br />
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|
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SNP: rs145116688,
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|
|
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gnomAD: rs145116688,
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|
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|
|
ClinVar: RCV000197441, RCV000456662, RCV001013787, RCV005016554
|
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|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with fumarate hydratase deficiency (FMRD; 606812), Grocott et al. (2020) identified compound heterozygous mutations in the FH gene: a c.94A-G transition in exon 2, resulting in an asp65-to-gly (D65G) substitution, and a 1-bp deletion (c.1293delA; 136850.0015) in exon 9, resulting in a frameshift and premature termination (Glu432LysfsTer17). The mutations were identified by sequencing of the FH gene and the parents were found to be mutation carriers. Urine organic acids in the patient demonstrated elevated fumaric acid, and cytosolic and mitochondrial fumarase enzyme activities were decreased in patient fibroblasts. Fumarase enzyme was purified from plasmids containing FH with each of the patient's mutations. Fumarase with the c.1293delA mutation had defective enzyme activity and oligomerization. Fumarase with the D65G mutation had a lower catalytic activity compared to wildtype. The patient's father, who carried the c.1293delA mutation, had a history of renal cell cancer, and her mother, who carried the D65G mutation, had a history of uterine leiomyomas. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0015 FUMARASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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|
FH, 1-BP DEL, 1293A
|
|
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<br />
|
|
|
|
SNP: rs398123163,
|
|
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|
|
|
gnomAD: rs398123163,
|
|
|
|
|
|
ClinVar: RCV000078145, RCV000445588, RCV000461548, RCV000493624
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.1293delA) in exon 9 of the FH gene, resulting in a frameshift and premature termination (Glu432LysfsTer17), that was identified in compound heterozygous state in a patient with fumarate hydratase deficiency (FMRD; 606812) by Grocott et al. (2020), see 136850.0014. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
|
</div>
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</div>
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Busby et al. (1976); Edwards and Hopkinson (1979); Petrova-Benedict
|
|
et al. (1987); Tolley and Craig (1975); van Someren et al. (1974)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Alam, N. A., Rowan, A. J., Wortham, N. C., Pollard, P. J., Mitchell, M., Tyrer, J. P., Barclay, E., Calonje, E., Manek, S., Adams, S. J., Bowers, P. W., Burrows, N. P., and 18 others.
|
|
<strong>Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.</strong>
|
|
Hum. Molec. Genet. 12: 1241-1252, 2003.
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[PubMed: 12761039]
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[Full Text: https://doi.org/10.1093/hmg/ddg148]
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<p class="mim-text-font">
|
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Barker, K. T., Bevan, S., Wang, R., Lu, Y.-J., Flanagan, A. M., Bridge, J. A., Fisher, C., Finlayson, C. J., Shipley, J., Houlston, R. S.
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<strong>Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.</strong>
|
|
Brit. J. Cancer 87: 446-448, 2002.
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[PubMed: 12177782]
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[Full Text: https://doi.org/10.1038/sj.bjc.660502]
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<li>
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<p class="mim-text-font">
|
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Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P.
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|
<strong>Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.</strong>
|
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J. Clin. Invest. 93: 2514-2518, 1994.
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[PubMed: 8200987]
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[Full Text: https://doi.org/10.1172/JCI117261]
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<li>
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<p class="mim-text-font">
|
|
Bourgeron, T., Chretien, D., Rotig, A., Munnich, A., Landrieu, P., Rustin, P.
|
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<strong>Molecular characterization of fumarase deficiency in two children with progressive encephalopathy. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 53 (suppl.): A891 only, 1993.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Busby, N., Courval, J., Francke, U.
|
|
<strong>Regional assignments of the genes for fumarate hydratase and guanylate kinase on chromosome 1 and for lysosomal acid phosphatase and esterase A4 on chromosome 11.</strong>
|
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Cytogenet. Cell Genet. 16: 105-107, 1976.
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[PubMed: 185008]
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[Full Text: https://doi.org/10.1159/000130565]
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</p>
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<li>
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<p class="mim-text-font">
|
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Carvajal-Carmona, L. G., Alam, N. A., Pollard, P. J., Jones, A. M., Barclay, E., Wortham, N., Pignatelli, M., Freeman, A., Pomplun, S., Ellis, I., Poulsom, R., El-Bahrawy, M. A., Berney, D. M., Tomlinson, I. P. M.
|
|
<strong>Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations.</strong>
|
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J. Clin. Endocr. Metab. 91: 3071-3075, 2006.
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[PubMed: 16757530]
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[Full Text: https://doi.org/10.1210/jc.2006-0183]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Chan, I., Wong, T., Martinez-Mir, A., Christiano, A. M., McGrath, J. A.
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|
<strong>Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.</strong>
|
|
Clin. Exp. Derm. 30: 75-78, 2005.
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[PubMed: 15663510]
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[Full Text: https://doi.org/10.1111/j.1365-2230.2004.01675.x]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Coughlin, E. M., Chalmers, R. A., Slaugenhaupt, S. A., Gusella, J. F., Shih, V. E., Ramesh, V.
|
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<strong>Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993.
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|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Craig, I., Tolley, E., Bobrow, M.
|
|
<strong>Mitochondrial and cytoplasmic forms of fumarate hydratase assigned to chromosome 1.</strong>
|
|
Cytogenet. Cell Genet. 16: 118-121, 1976.
|
|
|
|
|
|
[PubMed: 975868]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1159/000130569]
|
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|
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</p>
|
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</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Despoisses, S., Noel, L., Choiset, A., Portnoi, M.-F., Turleau, C., Quack, B., Taillemite, J.-L., de Grouchy, J., Junien, C.
|
|
<strong>Regional mapping of FH to band 1q42.1 by gene dosage studies. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 37: 450-451, 1984.
|
|
|
|
</p>
|
|
</li>
|
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<li>
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<p class="mim-text-font">
|
|
Doonan, S., Barra, D., Bossa, F.
|
|
<strong>Structural and genetic relationships between cytosolic and mitochondrial isoenzymes.</strong>
|
|
Int. J. Biochem. 16: 1193-1199, 1984.
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[PubMed: 6397370]
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[Full Text: https://doi.org/10.1016/0020-711x(84)90216-7]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Edwards, Y. H., Hopkinson, D. A.
|
|
<strong>Further characterization of the human fumarase variant, FH2-1.</strong>
|
|
Ann. Hum. Genet. 43: 103-108, 1979.
|
|
|
|
|
|
[PubMed: 525970]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1469-1809.1979.tb02002.x]
|
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Edwards, Y. H., Hopkinson, D. A.
|
|
<strong>The genetic determination of fumarase isozymes in human tissues.</strong>
|
|
Ann. Hum. Genet. 42: 303-313, 1979.
|
|
|
|
|
|
[PubMed: 434773]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1469-1809.1979.tb00664.x]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. P. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., Gottlieb, E.
|
|
<strong>Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.</strong>
|
|
Nature 477: 225-228, 2011.
|
|
|
|
|
|
[PubMed: 21849978]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature10363]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others.
|
|
<strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong>
|
|
J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.
|
|
|
|
|
|
[PubMed: 21398687]
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|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2010.085068]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Grocott, O., Phanor, S. K., Fung, F., Thibert, R. L., Berkmen, M. B.
|
|
<strong>Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.</strong>
|
|
Am. J. Med. Genet. 182A: 504-507, 2020.
|
|
|
|
|
|
[PubMed: 31746132]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.61415]
|
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Gross, K. L., Panhuysen, C. I. M., Kleinman, M. S., Goldhammer, H., Jones, E. S., Nassery, N., Stewart, E. A., Morton, C. C.
|
|
<strong>Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.</strong>
|
|
Genes Chromosomes Cancer 41: 183-190, 2004.
|
|
|
|
|
|
[PubMed: 15334541]
|
|
|
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|
|
[Full Text: https://doi.org/10.1002/gcc.20079]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Heinritz, W., Paasch, U., Sticherling, M., Wittekind, C., Simon, J. C., Froster, U. G., Renner, R.
|
|
<strong>Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC).</strong>
|
|
Ann. Hum. Genet. 72: 35-40, 2008.
|
|
|
|
|
|
[PubMed: 17908262]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1469-1809.2007.00396.x]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Kinsella, B. T., Doonan, S.
|
|
<strong>Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver.</strong>
|
|
Biosci. Rep. 6: 921-929, 1986.
|
|
|
|
|
|
[PubMed: 3828494]
|
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|
|
[Full Text: https://doi.org/10.1007/BF01116247]
|
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</p>
|
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</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Kiuru, M., Lehtonen, R., Eerola, H., Aittomaki, K., Blomqvist, C., Nevanlinna, H., Aaltonen, L. A., Launonen, V.
|
|
<strong>No germline FH mutations in familial breast cancer patients.</strong>
|
|
Europ. J. Hum. Genet. 13: 506-509, 2005.
|
|
|
|
|
|
[PubMed: 15523491]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201326]
|
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</p>
|
|
</li>
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<strong>Presence of two forms of fumarase (fumarate hydratase EC 4.2.1.2) in mammalian cells: immunological characterisation and genetic analysis in somatic cell hybrids; confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1.</strong>
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<strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong>
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<strong>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.</strong>
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van Someren, H., Beyersbergen van Henegouwen, H., de Wit, J.
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<strong>Evidence for synteny between the human loci for fumarate hydratase, UDG glucose pyrophosphorylase, 6-phosphogluconate dehydrogenase, phosphoglucomutase-1, and peptidase-C in man-Chinese hamster somatic cell hybrids.</strong>
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Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R.
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