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Entry
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- *608107 - MEFV INNATE IMMUNITY REGULATOR, PYRIN; MEFV
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- OMIM
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<p>
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<span class="h4">*608107</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</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/608107">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000103313;t=ENST00000219596" 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=4210" 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=608107" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000103313;t=ENST00000219596" 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_000243,NM_001198536" 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_000243" 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=608107" 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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</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=02012&isoform_id=02012_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/MEFV" 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/2407316,2415583,2808660,4557743,4588600,8928170,15419954,15419956,75517109,75517693,119605788,119605789,148283604,194384844,258589095,258589097,258589099,258589101,258589103,258589105,390190125,1788556990" 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/O15553" 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=4210" 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=ENSG00000103313;t=ENST00000219596" 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=MEFV" 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=MEFV" 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+4210" 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/MEFV" 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:4210" 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/4210" 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=chr16&hgg_gene=ENST00000219596.6&hgg_start=3242027&hgg_end=3256633&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:6998" 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:6998" 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/mefv" 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=608107[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=608107[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000103313" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=MEFV" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=MEFV" 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=MEFV" 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://fmf.igh.cnrs.fr/infevers/" 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=MEFV&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/PA30736" 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:6998" 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://www.mousephenotype.org/data/genes/MGI:1859396" 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/MEFV#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:1859396" 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/4210/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=4210" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00015114;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00015114 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00016190;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00016190 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00016191;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00016191 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00018384;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00018384 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022868;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022868 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022870;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022870 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022872;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022872 </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 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:608107" 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:4210" 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=MEFV&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> 12579009, 84625002<br />
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<strong>ICD10CM:</strong> L98.2, M04.1<br />
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<strong>ICD9CM:</strong> 277.31<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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608107
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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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MEFV INNATE IMMUNITY REGULATOR, PYRIN; MEFV
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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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FAMILIAL MEDITERRANEAN FEVER GENE<br />
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PYRIN<br />
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MARENOSTRIN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MEFV" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MEFV</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/16/138?start=-3&limit=10&highlight=138">16p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:3242027-3256633&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'})">16:3,242,027-3,256,633</a> </span>
|
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</em>
|
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</strong>
|
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<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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Familial Mediterranean fever, AD
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Familial Mediterranean fever, AR
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<li><a href="/graph/radial/608107" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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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>The MEFV gene encodes pyrin, which functions as an innate immune sensor that can trigger formation of an inflammasome, allowing the production of inflammatory mediators during infection (summary by <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27030597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning, the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> identified a gene from a 115-kb familial Mediterranean fever (<a href="/entry/249100">249100</a>) candidate interval on chromosome 16p. The novel gene encoded a 3.7-kb transcript that was expressed almost exclusively in mature granulocytes. The predicted 781-amino acid protein, which they termed pyrin, is a member of a family of nuclear factors homologous to the Ro52 antigen (<a href="/entry/109092">109092</a>) and the RET finger protein (RFP; <a href="/entry/602165">602165</a>). Northern blot analysis showed expression in peripheral blood, but there was no significant expression in 14 other normal tissues, including spleen, thymus, and lymph nodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288758" 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>Simultaneously and independently, the <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> identified transcriptional units in a critical MEFV interval of 60 kb on the basis of genomic sequence analysis and exon trapping. They identified 4 genes, one of which encoded pyrin, which this consortium designated marenostrin (from the Latin name of the Mediterranean Sea, mare nostrum). The C terminus of the deduced protein showed similarities to those of RET finger protein and butyrophilin (<a href="/entry/601610">601610</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288094" 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="#41" class="mim-tip-reference" title="Papin, S., Duquesnoy, P., Cazeneuve, C., Pantel, J., Coppey-Moisan, M., Dargemont, C., Amselem, S. <strong>Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus.</strong> Hum. Molec. Genet. 9: 3001-3009, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11115844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11115844</a>] [<a href="https://doi.org/10.1093/hmg/9.20.3001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11115844">Papin et al. (2000)</a> described the isolation and expression of a novel human MEFV isoform, MEFV-d2, generated by in-frame alternative splicing of exon 2. This transcript, expressed in leukocytes, predicts a 570-residue protein designated marenostrin-d2. Unlike the full-length protein (marenostrin-fl), which is distributed homogeneously over the entire cytoplasm, marenostrin-d2 concentrates into the nucleus. Deletion of the putative nuclear localization signals did not alter the nuclear localization of marenostrin-d2, whereas deletion of the domain encoded by the exon 1-exon 3 splice junction disrupted this localization. The authors hypothesized that MEFV encodes a nuclear protein and that MEFV alternative splicing may control functions of wildtype and mutant marenostrin proteins by regulating their translocation to the nucleus. <a href="#33" class="mim-tip-reference" title="Mansfield, E., Chae, J. J., Komarow, H. D., Brotz, T. M., Frucht, D. M., Aksentijevich, I., Kastner, D. L. <strong>The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments.</strong> Blood 98: 851-859, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468188</a>] [<a href="https://doi.org/10.1182/blood.v98.3.851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468188">Mansfield et al. (2001)</a> reported results of studies of the subcellular localization of wildtype pyrin that did not support the proposed nuclear or Golgi localization. They demonstrated colocalization with microtubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11468188+11115844" 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="#24" class="mim-tip-reference" title="Goulielmos, G. N., Fragouli, E., Aksentijevich, I., Sidiropoulos, P., Boumpas, D. T., Eliopoulos, E. <strong>Mutational analysis of the PRYSPRY domain of pyrin and implications for familial Mediterranean fever (FMF).</strong> Biochem. Biophys. Res. Commun. 345: 1326-1332, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16730661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16730661</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.04.185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16730661">Goulielmos et al. (2006)</a> reported that the human pyrin protein contains several conserved domains, including an N-terminal pyrin domain (PYD), followed by a bZIP transcription factor basic domain, a B-box zinc finger coiled-coil domain, and a C-terminal PRYSPRY domain. The B-box zinc finger coiled-coil domain is involved in homo- or heterodimer formation, and the PRYSPRY domain is involved in protein-protein interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16730661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning, the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> identified the MEFV gene on chromosome 16p. <a href="#12" class="mim-tip-reference" title="Chae, J. J., Centola, M., Aksentijevich, I., Dutra, A., Tran, M., Wood, G., Nagaraju, K., Kingma, D. W., Liu, P. P., Kastner, D. L. <strong>Isolation, genomic organization, and expression analysis of the mouse and rat homologs of MEFV, the gene for familial Mediterranean fever.</strong> Mammalian Genome 11: 428-435, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10818206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10818206</a>] [<a href="https://doi.org/10.1007/s003350010082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10818206">Chae et al. (2000)</a> localized the mouse Mefv gene to chromosome 16, region A3-B1, thus extending a region of syntenic homology with human 16p13.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9288758+10818206" 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="#11" class="mim-tip-reference" title="Centola, M., Wood, G., Frucht, D. M., Galon, J., Aringer, M., Farrell, C., Kingma, D. W., Horwitz, M. E., Mansfield, E., Holland, S. M., O'Shea, J. J., Rosenberg, H. F., Malech, H. L., Kastner, D. L. <strong>The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.</strong> Blood 95: 3223-3231, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807793</a>]" pmid="10807793">Centola et al. (2000)</a> presented data placing the MEFV gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an interferon-gamma immediate early gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807793" 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="#33" class="mim-tip-reference" title="Mansfield, E., Chae, J. J., Komarow, H. D., Brotz, T. M., Frucht, D. M., Aksentijevich, I., Kastner, D. L. <strong>The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments.</strong> Blood 98: 851-859, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468188</a>] [<a href="https://doi.org/10.1182/blood.v98.3.851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468188">Mansfield et al. (2001)</a> demonstrated colocalization of wildtype pyrin with microtubules. Deletion constructs showed that the unique N-terminal domain of pyrin is necessary and sufficient for the colocalization of pyrin with microtubules. By phalloidin staining, colocalization of pyrin with actin was also observed in perinuclear filaments and in peripheral lamellar ruffles. The authors proposed that pyrin regulates inflammatory responses at the level of leukocyte cytoskeletal organization and that the unique therapeutic effect of colchicine in FMF may be dependent on this interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468188" 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 study the physiologic role of pyrin, <a href="#13" class="mim-tip-reference" title="Chae, J. J., Komarow, H. D., Cheng, J., Wood, G., Raben, N., Liu, P. P., Kastner, D. L. <strong>Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis.</strong> Molec. Cell 11: 591-604, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12667444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12667444</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00056-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12667444">Chae et al. (2003)</a> generated mice expressing a truncated pyrin molecule that, similar to FMF patients, retained the full PYRIN domain. Bacterial lipopolysaccharide (LPS) induced accentuated body temperatures and increased lethality in homozygous mutant mice. When stimulated, macrophages from these mice produced increased amounts of activated caspase-1 and, consequently, elevated levels of mature Il1b. Full-length pyrin competed in vitro with caspase-1 for binding to Asc (<a href="/entry/606838">606838</a>), a caspase-1 activator. Apoptosis was impaired in macrophages from pyrin-truncation mice through an IL1-independent pathway. These results supported a critical role for pyrin in the innate immune response, possibly by acting on ASC, and suggested a biologic basis for the selection of hypomorphic pyrin variants in man. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12667444" 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 a yeast 2-hybrid assay, <a href="#44" class="mim-tip-reference" title="Shoham, N. G., Centola, M., Mansfield, E., Hull, K. M., Wood, G., Wise, C. A., Kastner, D. L. <strong>Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.</strong> Proc. Nat. Acad. Sci. 100: 13501-13506, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14595024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14595024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14595024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2135380100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14595024">Shoham et al. (2003)</a> showed that human pyrin and human PSTPIP1 (<a href="/entry/606347">606347</a>) interacted with each other and colocalized within peripheral blood granulocytes and monocytes. Tyrosine phosphorylation of PSTPIP1 markedly increased binding to pyrin. Expression of 2 PSTPIP1 mutations (<a href="/entry/606347#0001">606347.0001</a> and <a href="/entry/606347#0002">606347.0002</a>) associated with PAPA syndrome (<a href="/entry/604416">604416</a>) resulted in increased PSTPIP1-pyrin binding. <a href="#44" class="mim-tip-reference" title="Shoham, N. G., Centola, M., Mansfield, E., Hull, K. M., Wood, G., Wise, C. A., Kastner, D. L. <strong>Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.</strong> Proc. Nat. Acad. Sci. 100: 13501-13506, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14595024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14595024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14595024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.2135380100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14595024">Shoham et al. (2003)</a> suggested that sequestration of pyrin in PAPA syndrome may prevent pyrin's normal immunoregulatory functions, resulting in an excess of IL1-beta production, as found in a patient with PAPA syndrome. The findings elucidated another pathway involved in regulating inflammation, and linked PAPA syndrome and familial Mediterranean fever as disorders arising from defects within the same pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14595024" 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 coimmunoprecipitation analysis, <a href="#14" class="mim-tip-reference" title="Chae, J. J., Wood, G., Masters, S. L., Richard, K., Park, G., Smith, B. J., Kastner, D. L. <strong>The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate Il-1-beta production.</strong> Proc. Nat. Acad. Sci. 103: 9982-9987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16785446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16785446</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16785446[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0602081103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16785446">Chae et al. (2006)</a> demonstrated direct interaction between pyrin and caspase-1 (CASP1; <a href="/entry/147678">147678</a>) that was independent of ASC. Mutation analysis showed that the C-terminal B30.2 domain of pyrin was necessary and sufficient for binding with CASP1. Constructs of the B30.2 domain of wildtype pyrin, but not constructs harboring FMF-associated mutations in the B30.2 domain (i.e., M694V; <a href="#0001">608107.0001</a>), bound CASP1 strongly and inhibited IL1B (<a href="/entry/147720">147720</a>) secretion. Knockdown of pyrin in THP-1 cells by MEFV small interfering RNA caused increased IL1B secretion in response to lipopolysaccharide. Computational modeling confirmed the interaction between the p10 and p20 subunits of CASP1 and pyrin B30.2. Treatment of a patient refractory to colchicine and homozygous for M694V with anakinra, a recombinant IL1R antagonist (IL1RN; <a href="/entry/147679">147679</a>), controlled serum amyloid A (SAA1; <a href="/entry/104750">104750</a>) and C-reactive protein (CRP; <a href="/entry/123260">123260</a>) levels. <a href="#14" class="mim-tip-reference" title="Chae, J. J., Wood, G., Masters, S. L., Richard, K., Park, G., Smith, B. J., Kastner, D. L. <strong>The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate Il-1-beta production.</strong> Proc. Nat. Acad. Sci. 103: 9982-9987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16785446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16785446</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16785446[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0602081103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16785446">Chae et al. (2006)</a> concluded that wildtype pyrin inhibits CASP1 activation. They proposed that FMF-associated mutations have less of an inhibitory effect on CASP1 activation and may have been selected in human history because of the resulting increase in innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16785446" 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="#48" class="mim-tip-reference" title="Yu, J.-W., Fernandes-Alnemri, T., Datta, P., Wu, J., Juliana, C., Solorzano, L., McCormick, M., Zhang, Z., Alnemri, E. S. <strong>Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants.</strong> Molec. Cell 28: 214-227, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17964261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17964261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17964261[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.08.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17964261">Yu et al. (2007)</a> found that both pyrin and PSTPIP1 formed homotrimers, and that the pyrin homotrimer was inactive due to masking of its PYD motif by its B box. PSTPIP1 activated pyrin by binding to its B box and unmasking the PYD, leading to interaction of the PYD with ASC, ASC dimerization, and recruitment and activation of caspase-1. Autoinflammatory PSTPIP1 mutants had higher binding affinities for the pyrin B box than did wildtype PSTPIP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17964261" 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="#25" class="mim-tip-reference" title="Grandemange, S., Soler, S., Touitou, I. <strong>Expression of the familial Mediterranean fever gene is regulated by nonsense-mediated decay.</strong> Hum. Molec. Genet. 18: 4746-4755, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19755381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19755381</a>] [<a href="https://doi.org/10.1093/hmg/ddp437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19755381">Grandemange et al. (2009)</a> examined the effect of indirect and direct inhibition of nonsense-mediated decay (NMD) on expression of the MEFV transcripts in THP1, monocyte, and neutrophil cells. MEFV was regulated by NMD in both a cell- and transcript-specific manner. The authors suggested the possibility of translation of alternatively spliced MEFV transcripts into several pyrin variants according to cell type and inflammatory state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19755381" 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="#46" class="mim-tip-reference" title="Xu, H., Yang, J., Gao, W., Li, L., Li, P., Zhang, L., Gong, Y.-N., Peng, X., Xi, J. J., Chen, S., Wang, F., Shao, F. <strong>Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome.</strong> Nature 513: 237-241, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919149</a>] [<a href="https://doi.org/10.1038/nature13449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919149">Xu et al. (2014)</a> showed that pyrin mediates CASP1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. <a href="#46" class="mim-tip-reference" title="Xu, H., Yang, J., Gao, W., Li, L., Li, P., Zhang, L., Gong, Y.-N., Peng, X., Xi, J. J., Chen, S., Wang, F., Shao, F. <strong>Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome.</strong> Nature 513: 237-241, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919149</a>] [<a href="https://doi.org/10.1038/nature13449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919149">Xu et al. (2014)</a> further demonstrated that Burkholderia cenocepacia inactivates RHOA (<a href="/entry/165390">165390</a>) by deamidating asparagine-41, also in the switch-I region, and thereby triggers pyrin inflammasome activation, both of which require the bacterial type VI secretion system. Loss of the pyrin inflammasome causes elevated intramacrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, <a href="#46" class="mim-tip-reference" title="Xu, H., Yang, J., Gao, W., Li, L., Li, P., Zhang, L., Gong, Y.-N., Peng, X., Xi, J. J., Chen, S., Wang, F., Shao, F. <strong>Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome.</strong> Nature 513: 237-241, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919149</a>] [<a href="https://doi.org/10.1038/nature13449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919149">Xu et al. (2014)</a> concluded that pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a paradigm in mammalian innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24919149" 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="#43" class="mim-tip-reference" title="Sharma, D., Malik, A., Guy, C., Vogel, P., Kanneganti, T.-D. <strong>TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy.</strong> J. Clin. Invest. 129: 150-162, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30457980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30457980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30457980[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI121372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30457980">Sharma et al. (2019)</a> found that Tnf (<a href="/entry/191160">191160</a>) signaling promoted pyrin expression and inflammasome activation in response to multiple stimuli in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30457980" 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="#32" class="mim-tip-reference" title="Magupalli, V. G., Negro, R., Tian, Y., Hauenstein, A. V., Di Caprio, G., Skillern, W., Deng, Q., Orning, P., Alam, H. B., Maliga, Z., Sharif, H., Hu, J. J., Evavold, C. L., Kagan, J. C., Schmidt, F. I., Fitzgerald, K. A., Kirchhausen, T., Li, Y., Wu, H. <strong>HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.</strong> Science 369: eaas8995, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943500</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32943500[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/10.1126/science.aas8995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32943500">Magupalli et al. (2020)</a> showed that NLRP3 (<a href="/entry/606416">606416</a>)- and pyrin-mediated inflammasome assembly, caspase activation, and IL1-beta conversion occurred at the microtubule-organizing center (MTOC) in mouse and human cells. HDAC6 (<a href="/entry/300272">300272</a>) was required for microtubule transport and assembly of these inflammasomes both in vitro and in mice. The authors noted that because HDAC6 can transport ubiquitinated pathologic aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for downregulation of these inflammasomes by autophagy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943500" 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="#24" class="mim-tip-reference" title="Goulielmos, G. N., Fragouli, E., Aksentijevich, I., Sidiropoulos, P., Boumpas, D. T., Eliopoulos, E. <strong>Mutational analysis of the PRYSPRY domain of pyrin and implications for familial Mediterranean fever (FMF).</strong> Biochem. Biophys. Res. Commun. 345: 1326-1332, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16730661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16730661</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.04.185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16730661">Goulielmos et al. (2006)</a> constructed a 3-dimensional model of the PRYSPRY domain of pyrin. The core of the PRYSPRY domain consists of a 5-strand and 7-strand beta sandwich that is surrounded by linking loops. A hydrophobic binding cavity is formed by 1 external side of the beta sandwich and several loops. The authors localized the most frequent pyrin mutations in MEFV to the PRYSPRY domain model and classified them according to disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16730661" 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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By screening 165 individuals from 65 families with familial Mediterranean fever, the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> identified 3 different missense mutations in exon 10 of the MEFV gene (<a href="#0001">608107.0001</a>, <a href="#0003">608107.0003</a>, <a href="#0004">608107.0004</a>) that accounted for 78 carrier chromosomes. The authors noted that none of the identified mutations resulted in a truncated protein, and they suggested that the periodic nature of inflammatory attacks in FMF is consistent with a protein that functions adequately at steady state but decompensates under stress. The <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> identified 4 sequence variations (<a href="#0001">608107.0001</a>-<a href="#0004">608107.0004</a>) in the marenostrin gene that correlated with FMF in various ethnic groups. In 72% of the patients in their sample, 1 or 2 of the 4 mutations were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9288094+9288758" 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="#23" class="mim-tip-reference" title="Gershoni-Baruch, R., Shinawi, M., Shamaly, H., Katsinetz, L., Brik, R. <strong>Familial Mediterranean fever: The segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability.</strong> Am. J. Med. Genet. 109: 198-201, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11977178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11977178</a>] [<a href="https://doi.org/10.1002/ajmg.10352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11977178">Gershoni-Baruch et al. (2002)</a> reported a family in which 4 different MEFV mutations were segregating: V726A (<a href="#0003">608107.0003</a>), M694V (<a href="#0001">608107.0001</a>), M680I (<a href="#0004">608107.0004</a>), and K695R (<a href="#0010">608107.0010</a>). Three parents and 1 grandparent who each carried 2 mutated alleles remained asymptomatic. Of 9 grandchildren who were compound heterozygotes for 2 mutations in the MEFV gene, only those with either the M694V/V726A or the M694V/M680I genotypes manifested the disease, bearing evidence of the severity of M694V in individuals sharing a similar genetic and environmental background. Nevertheless, 1 father and 1 grandmother who carried the M694V/V726A compound heterozygous genotype were symptom-free, while 4 grandchildren of the same genotype manifested the disease from an early age, suggesting a role of additional environmental and genetic modifiers. The occurrence of 4 different mutations in 2 sets of consanguineous parents was a remarkable finding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11977178" 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>Acute Febrile Neutrophilic Dermatosis</em></strong></p><p>
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In 12 affected members of a large 3-generation Belgian family with acute febrile neutrophilic dermatosis (AFND; <a href="/entry/608068">608068</a>), <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> identified a heterozygous missense mutation in exon 2 of the MEFV gene (S242R; <a href="#0021">608107.0021</a>). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous S242R mutation was subsequently identified in 3 additional pedigrees with an overlapping phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation enhanced the formation of ASC (PYCARD; <a href="/entry/606838">606838</a>) compared to controls. Downstream of ASC, the S242R mutations resulted in activation of CASP1 (<a href="/entry/147678">147678</a>) as well as increased secretion of IL1B compared to wildtype. Further studies showed that the mutation impaired phosphorylation of S242, which resulted in removal of inhibitory 14-3-3 proteins (see, e.g., <a href="/entry/609009">609009</a> and <a href="/entry/605066">605066</a>) and constitutive activation of pyrin. One patient was successfully treated with anakinra, which blocks IL1RA. <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> noted that the molecular mechanism resulting from the S242R mutation differed from that of FMF-associated mutations M694V, M680I, and V726A, which had no appreciable effect on 14-3-3 binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27030597" 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 affected members of a Spanish family with AFND, <a href="#38" class="mim-tip-reference" title="Moghaddas, F., Llamas, R., De Nardo, D., Martinez-Banaclocha, H., Martinez-Garcia, J. J. Mesa-del-Castillo, P., Baker, P. J., Gargallo, V., Mensa-Vilaro, A., Canna, S., Wicks, I. P., Pelegrin, P., Arostegui, J. I., Masters, S. L. <strong>A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to familial Mediterranean fever.</strong> Ann. Rheum. Dis. 76: 2085-2094, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28835462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28835462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28835462[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/annrheumdis-2017-211473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28835462">Moghaddas et al. (2017)</a> identified a heterozygous missense mutation in exon 2 of the MEFV gene (E244K; <a href="#0022">608107.0022</a>). The mutation, which was found by direct sequencing of the MEFV gene, was not found in the 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in 250 healthy Spanish controls. Patient-derived monocytes and cells transfected with the mutation showed augmented ASC speck formation both at baseline and upon LPS exposure, increased CASP1 activity, increased IL1B and IL18, and increased inflammatory cell death compared to controls, consistent with activation of the inflammasome. These findings were associated with reduced phosphorylation of the MEFV 14-3-3 binding motif and reduced 14-3-3 binding compared to controls, ultimately resulting in inappropriate activation of MEFV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28835462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> suggested that phenotypic differences may be related to different mutations. The M694V mutation (<a href="#0001">608107.0001</a>) was frequent in populations with a higher incidence of systemic amyloidosis, whereas the V726A mutation (<a href="#0003">608107.0003</a>) was found in a population in which amyloidosis is less common. They also suggested that a heterozygous selective advantage based on heightened inflammatory response to some pathogen or class of pathogens endemic in the Mediterranean may be responsible for the high gene frequencies for FMF in populations in that area. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288758" 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="#31" class="mim-tip-reference" title="Livneh, A., Aksentijevich, I., Langevitz, P., Torosyan, Y., G-Shoham, N., Shinar, Y., Pras, E., Zaks, N., Padeh, S., Kastner, D. L., Pras, M. <strong>A single mutated MEFV allele in Israeli parents suffering from familial Mediterranean fever and Behcet's disease (FMF-BD).</strong> Europ. J. Hum. Genet. 9: 191-196, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313758</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313758">Livneh et al. (2001)</a> studied 8 patients with FMF who also had Behcet disease (BD; <a href="/entry/109650">109650</a>). Sequence analysis of the MEFV gene revealed that all 8 patients had only a single mutated allele. The patients' noncarrier chromosomes converged into 3 different MEFV haplotypes and were shared by unaffected heterozygous family members. The findings did not support a role for the noncarrier chromosome in the induction of FMF, and suggested that Behcet disease may induce the expression of FMF in carriers, despite the known recessive mode of inheritance. In the 8 families studied, Behcet disease was found in 10 of 11 heterozygous FMF patients versus 1 of 16 heterozygous unaffected individuals (P less than 0.001). <a href="#31" class="mim-tip-reference" title="Livneh, A., Aksentijevich, I., Langevitz, P., Torosyan, Y., G-Shoham, N., Shinar, Y., Pras, E., Zaks, N., Padeh, S., Kastner, D. L., Pras, M. <strong>A single mutated MEFV allele in Israeli parents suffering from familial Mediterranean fever and Behcet's disease (FMF-BD).</strong> Europ. J. Hum. Genet. 9: 191-196, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313758</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313758">Livneh et al. (2001)</a> hypothesized that a reduced level of functional pyrin, presumably characterizing heterozygosity, and an increased demand for pyrin by activated granulocytes of Behcet disease, may ultimately lead to FMF attacks. The authors also noted the possibility that not all patients with FMF conform to a recessive mode of inheritance, and that Behcet disease may be only one example of various inflammatory, infectious, and other stimuli predisposing carriers of a mutated MEFV gene to acute attacks of FMF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313758" 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="#45" class="mim-tip-reference" title="Touitou, I. <strong>The spectrum of familial Mediterranean fever (FMF) mutations.</strong> Europ. J. Hum. Genet. 9: 473-483, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11464238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11464238</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11464238">Touitou (2001)</a> reviewed the spectrum of MEFV mutations reported in FMF. Of the 29 known mutations, 26 were missense mutations, 2 were small deletions, and 1 was a nonsense mutation. Three apparent mutation hotspots were identified at codons 148, 680, and 694. Five frequent founder mutations accounted for the majority (74%) of mutations, whereas the other 24 known mutations were found in no more than 1% of FMF chromosomes. About a quarter of all FMF alleles were unidentified. The M694V mutation (<a href="#0001">608107.0001</a>) was the most frequent mutation in the commonly affected populations of Arabs, Armenians, non-Ashkenazi Jews, and Turks, ranging from 20 to 65% of FMF chromosomes. The penetrance of M694V homozygosity was very high (99%) and correlated with a severe disease course with frequent amyloidosis, early disease onset, and arthritis. In contrast, the E148Q mutation (<a href="#0005">608107.0005</a>) was the least penetrant, with 55% asymptomatic cases at homozygosity. Amyloidosis had never been reported in those patients. The author concluded that the overall FMF phenotype is likely to be influenced by other genetic as well as nongenetic factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11464238" 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="#36" class="mim-tip-reference" title="Medlej-Hashim, M., Petit, I., Adib, S., Chouery, E., Salem, N., Delague, V., Rawashdeh, M., Mansour, I., Lefranc, G., Naman, R., Loiselet, J., Lecron, J.-C., Serre, J.-L., Megarbane, A. <strong>Familial Mediterranean fever: association of elevated IgD plasma levels with specific MEFV mutations.</strong> Europ. J. Hum. Genet. 9: 849-854, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781702</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781702">Medlej-Hashim et al. (2001)</a> attempted a genotype-phenotype correlation in FMF. They studied 147 unrelated Lebanese and Jordanian FMF patients and correlated IgD plasma level with specific phenotypic characteristics. The IgD plasma distribution in patients was similar to that of healthy subjects, which was not in favor of a direct effect of MEFV mutations on serum IgD levels. However, homozygote status for the M694V mutation (odds ratio, 6.25) and to a lesser extent V726A (OR, 2.2) increased the risk of higher IgD level when compared to other genotypes. Patients with higher IgD levels were more likely to suffer from arthritis (OR, 18). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781702" 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="#20" class="mim-tip-reference" title="Gershoni-Baruch, R., Brik, R., Shinawi, M., Livneh, A. <strong>The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever.</strong> Europ. J. Hum. Genet. 10: 145-149, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938447</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11938447">Gershoni-Baruch et al. (2002)</a> investigated 220 Jewish and Arab FMF patients from 178 unrelated families in whom both MEFV mutant alleles had been characterized. The M694V mutation (<a href="#0001">608107.0001</a>) accounted for the majority of FMF chromosomes (62.9% among unrelated patients). Mutations V726A (<a href="#0003">608107.0003</a>), M680I (<a href="#0004">608107.0004</a>), E148Q (<a href="#0005">608107.0005</a>), M694I (<a href="#0002">608107.0002</a>), and the complex V726A-E148Q allele accounted for 13.8%, 7.6%, 5.3%, 5.3%, and 5.1% of FMF chromosomes, respectively. One hundred and five patients homozygous for the M694V mutation scored higher on disease severity, manifested more frequently articular and renal manifestations, and consumed higher doses of colchicine to control their attacks, compared to 39 patients compound heterozygous for M694V with either mutations V726A, M680I, or E148Q and compared to 15 homozygous for V726A or M680I. Compared to 12 V726A-E148Q homozygotes, M694V homozygotes did not differ on any of these effects other than the frequency of arthritis, which was higher among M694V homozygotes. Of the 42 patients with amyloidosis, 32 were M694V homozygotes, 4 were V726A-E148Q homozygotes, and the remaining 6 were compound heterozygotes for 1 of these alleles. The morbidity conferred by the complex V726A-E148Q allele by far outweighed that associated with the V726A allele, bearing evidence to the fact that the E148Q mutation is not a benign polymorphism. <a href="#20" class="mim-tip-reference" title="Gershoni-Baruch, R., Brik, R., Shinawi, M., Livneh, A. <strong>The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever.</strong> Europ. J. Hum. Genet. 10: 145-149, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938447</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11938447">Gershoni-Baruch et al. (2002)</a> concluded that the wide clinical variability of the disease seems to be partly affected by allelic heterogeneity and partly by additional genetic and/or environmental modifiers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11938447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Gershoni-Baruch, R., Brik, R., Zacks, N., Shinawi, M., Lidar, M., Livneh, A. <strong>The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.</strong> Arthritis Rheum. 48: 1149-1155, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687559</a>] [<a href="https://doi.org/10.1002/art.10944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687559">Gershoni-Baruch et al. (2003)</a> concluded that severity of FMF and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene. They found that the male:female ratio (1.3) was higher among patients with amyloidosis (1.8) than among patients without amyloidosis (1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio, 4.27), the presence of the homozygous SAA-alpha/alpha genotype (<a href="/entry/104750">104750</a>) (OR, 2.99), the occurrence of arthritis attacks (OR, 2.43), and male sex (OR 1.73) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12687559" 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="#7" class="mim-tip-reference" title="Booth, D. R., Booth, S. E., Gillmore, J. D., Hawkins, P. N., Pepys, M. B. <strong>SAA1 alleles as risk factors in reactive systemic AA amyloidosis.</strong> Amyloid 5: 262-265, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10036584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10036584</a>] [<a href="https://doi.org/10.3109/13506129809007299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10036584">Booth et al. (1998)</a> had found that the risk of developing secondary amyloidosis was higher in patients with rheumatoid arthritis or juvenile chronic arthritis when they carried the SAA1 alpha/alpha homozygous polymorphism of serum amyloid A1 (SAA1; <a href="/entry/104750">104750</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10036584" 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="#9" class="mim-tip-reference" title="Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Genevieve, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.-C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S. <strong>Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.</strong> Am. J. Hum. Genet. 67: 1136-1143, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017802</a>] [<a href="https://doi.org/10.1016/S0002-9297(07)62944-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017802">Cazeneuve et al. (2000)</a> noted that the variable risk for patients with identical MEFV mutations to develop renal amyloidosis suggested the role of modifying genetic and/or environmental factors. <a href="#9" class="mim-tip-reference" title="Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Genevieve, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.-C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S. <strong>Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.</strong> Am. J. Hum. Genet. 67: 1136-1143, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017802</a>] [<a href="https://doi.org/10.1016/S0002-9297(07)62944-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017802">Cazeneuve et al. (2000)</a> investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. They found that the alpha/alpha homozygous SAA1 genotype was associated with a 7-fold increased risk for renal amyloidosis, compared with other SAA1 genotypes. This association, which was present whatever the MEFV genotype, was particularly marked in patients homozygous for M694V. The risk for male patients of developing renal amyloidosis was 4-fold higher than that for female patients. Polymorphisms in the SAA2 (<a href="/entry/104751">104751</a>) or the APOE (<a href="/entry/107741">107741</a>) gene did not appear to influence susceptibility to renal amyloidosis. <a href="#9" class="mim-tip-reference" title="Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Genevieve, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.-C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S. <strong>Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.</strong> Am. J. Hum. Genet. 67: 1136-1143, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017802</a>] [<a href="https://doi.org/10.1016/S0002-9297(07)62944-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017802">Cazeneuve et al. (2000)</a> found that the presence of only 1 SAA1-alpha allele did not confer an increased susceptibility to renal amyloidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017802" 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="#39" class="mim-tip-reference" title="Nadeau, J. H. <strong>Modifier genes in mice and humans.</strong> Nature Rev. Genet. 2: 165-174, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11256068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11256068</a>] [<a href="https://doi.org/10.1038/35056009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11256068">Nadeau (2001)</a> discussed modifier genes in mice and humans, pointing out that these genes may modify the phenotype of mendelian traits by reducing penetrance, so-called dominance modification, and effects on expressivity and pleiotropy. The modification of FMF as to the occurrence of amyloidosis is an example of effects on pleiotropy. The SAA1 gene maps to 11p and the MEFV gene maps to 16p. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11256068" 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="#26" class="mim-tip-reference" title="Grossman, C., Kassel, Y., Livneh, A., Ben-Zvi, I. <strong>Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation.</strong> Europ. J. Med. Genet. 62: 103532, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30171907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30171907</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30171907">Grossman et al. (2019)</a> reported a comprehensive characterization of the phenotypes of 57 patients with FMF who were homozygous for the M694V mutation (<a href="#0001">608107.0001</a>) in the MEFV gene compared to the phenotypes of a cohort of 56 patients with FMF and other MEFV genotypes. <a href="#26" class="mim-tip-reference" title="Grossman, C., Kassel, Y., Livneh, A., Ben-Zvi, I. <strong>Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation.</strong> Europ. J. Med. Genet. 62: 103532, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30171907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30171907</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30171907">Grossman et al. (2019)</a> found that disease severity and average frequency of attacks per year, both before and after treatment, were higher in the M694V homozygote group compared to the cohort of patients with other MEFV genotypes, although there was no difference in the length of attacks or in the proportion of patients with abdominal, erysipelas-like erythema and fever-alone attacks. <a href="#26" class="mim-tip-reference" title="Grossman, C., Kassel, Y., Livneh, A., Ben-Zvi, I. <strong>Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation.</strong> Europ. J. Med. Genet. 62: 103532, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30171907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30171907</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30171907">Grossman et al. (2019)</a> also found that the colchicine dose was higher and the response to colchicine was lower in the M694V homozygote cohort. Additionally, the homozygote cohort had a higher overall rate of diseases associated with FMF, including Crohn disease, Behcet disease, ankylosing spondylitis and Henoch Schonlein purpura, but not fibromyalgia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30171907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> identified several disease-associated haplotypes, and found ancestral relationships among carrier chromosomes that had been separated for centuries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Chen, X., Fischel-Ghodsian, N., Cercek, A., Hamon, M., Ogur, G., Lotan, R., Danon, Y., Shohat, M. <strong>Assessment of pyrin gene mutations in Turks with familial Mediterranean fever (FMF).</strong> Hum. Mutat. 11: 456-460, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9603438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9603438</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<456::AID-HUMU6>3.0.CO;2-G" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9603438">Chen et al. (1998)</a> found that of 34 disease alleles in FMF patients of Turkish origin, 19 carried the met694-to-val mutation (<a href="#0001">608107.0001</a>) and 5 each carried the met680-to-ile (<a href="#0004">608107.0004</a>) and the val726-to-ala (<a href="#0003">608107.0003</a>) mutations. A mutation was not identified in 5 of the 34 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9603438" 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>Each of the 4 mutations that were first identified as the basis for FMF segregates with 1 ancestral haplotype and all are clustered in exon 10 (<a href="#0001">608107.0001</a>-<a href="#0004">608107.0004</a>). In a search for additional MEFV mutations in 120 apparently nonfounder FMF chromosomes, <a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed 8 novel mutations (see, e.g., <a href="#0005">608107.0005</a>) in exon 2 (E148Q, E167D, and T267I), exon 5 (F479L), and exon 10 (I692del, K695R, A744S, and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non-Ashkenazi Jews. Altogether, these new findings definitively established the marenostrin/pyrin-encoding gene as the MEFV locus responsible for FMF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" 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="Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L. <strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong> Am. J. Hum. Genet. 64: 949-962, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>] [<a href="https://doi.org/10.1086/302327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090880">Aksentijevich et al. (1999)</a> presented data on FMF mutations in non-Ashkenazi Jewish and Arab patients in whom they had not found mutations in earlier studies and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the 2 mutations that were novel, one (<a href="#0013">608107.0013</a>) caused the same amino acid change as a previously known mutation, M680I (<a href="#0004">608107.0004</a>), although the nucleotide change was different, and the other, P369S (<a href="#0014">608107.0014</a>), was located in exon 3 (all 4 of the mutations initially described in MEFV were in exon 10). Consistent with the findings of others, the E148Q (<a href="#0005">608107.0005</a>) mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicated an ancestral relationship between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicated reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helped account for recessive inheritance in an Ashkenazi family previously reported by <a href="#49" class="mim-tip-reference" title="Yuval, Y., Hemo-Zisser, M., Zemer, D., Sohar, E., Pras, M. <strong>Dominant inheritance in two families with familial Mediterranean fever (FMF).</strong> Am. J. Med. Genet. 57: 455-457, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677151</a>] [<a href="https://doi.org/10.1002/ajmg.1320570319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7677151">Yuval et al. (1995)</a> as an unusual case of dominantly inherited FMF. The presence of 3 frequent MEFV mutations in multiple Mediterranean populations strongly suggested a heterozygote advantage in this geographic region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7677151+10090880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Cazeneuve, C., Sarkisian, T., Pecheux, C., Dervichian, M., Nedelec, B., Reinert, P., Ayvazyan, A., Kouyoumdjian, J.-C., Ajrapetyan, H., Delpech, M., Goossens, M., Dode, C., Grateau, G., Amselem, S. <strong>MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype--genetic and therapeutic implications.</strong> Am. J. Hum. Genet. 65: 88-97, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364520</a>] [<a href="https://doi.org/10.1086/302459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364520">Cazeneuve et al. (1999)</a> investigated 90 Armenian FMF patients from 77 unrelated families who were not selected through genetic linkage analysis. They found that 8 mutations, one of which (R408Q; <a href="#0015">608107.0015</a>) was new, accounted for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V (<a href="#0001">608107.0001</a>) homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P = 0.0002 and P = 0.006, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364520" 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="Mansour, I., Delague, V., Cazeneuve, C., Dode, C., Chouery, E., Pecheux, C., Medlej-Hashim, M., Salem, N., El Zein, L., Levan-Petit, I., Lefranc, G., Goossens, M., Delpech, M., Amselem, S., Loiselet, J., Grateau, G., Megarbane, A., Naman, R. <strong>Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek Orthodoxes, Greek Catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.</strong> Europ. J. Hum. Genet. 9: 51-55, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175300</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175300">Mansour et al. (2001)</a> tested 79 Lebanese FMF patients for 15 mutations in the MEFV gene and found that they accounted for 67% of the total alleles. Mutations were detected in patients belonging to all Lebanese communities, including the Sunnite, Chiite, Druze, Maronite, Greek Orthodox, Greek Catholic, Syriac, and Armenian communities. The presence of FMF patients in this heterogeneous cohort of Lebanese patients supported the hypothesis of a selective advantage for FMF heterozygotes in the Mediterranean region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175300" 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="#47" class="mim-tip-reference" title="Yilmaz, E., Ozen, S., Balci, B., Duzova, A., Topaloglu, R., Besbas, N., Saatci, U., Bakkaloglu, A., Ozguc, M. <strong>Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population.</strong> Europ. J. Hum. Genet. 9: 553-555, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11464248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11464248</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11464248">Yilmaz et al. (2001)</a> tested 450 Turkish FMF patients for 5 common MEFV gene mutations (M694V, M680I, E148Q, V726A, and M694I). The mutations accounted for 67.7% of the MEFV alleles, with the M694V mutation accounting for 51.6% of the alleles. Screening for these 5 mutations in a Turkish population sample of 100 showed 1 compound heterozygote and 20 heterozygotes, giving an allele frequency of 11%. <a href="#22" class="mim-tip-reference" title="Gershoni-Baruch, R., Shinawi, M., Leah, K., Badarnah, K., Brik, R. <strong>Familial Mediterranean fever: prevalence, penetrance and genetic drift.</strong> Europ. J. Hum. Genet. 9: 634-637, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528510</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528510">Gershoni-Baruch et al. (2001)</a> examined 146 unrelated FMF patients of Jewish and Arab descent for the same 5 founder mutations. The mutations accounted for 91% of FMF chromosomes. The overall carrier rates for the 4 most common FMF mutations (M680I, M694V, V726A, and E148Q) were 1:4.5 in 407 Ashkenazi Jews, 1:4.7 in 243 Moroccan Jews, 1:3.5 in 205 Iraqi Jews, and 1:4.3 in 318 Muslim Arabs. The overall frequency of low-penetrant mutations E148Q and V726A indicated that most individuals who have a genetic diagnosis of FMF remain asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11528510+11464248" 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="#30" class="mim-tip-reference" title="Kogan, A., Shinar, Y., Lidar, M., Revivo, A., Langevitz, P., Padeh, S., Pras, M., Livneh, A. <strong>Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.</strong> Am. J. Med. Genet. 102: 272-276, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484206</a>] [<a href="https://doi.org/10.1002/ajmg.1438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484206">Kogan et al. (2001)</a> investigated the carrier rate of the most common MEFV mutations among different Jewish groups in Israel. Screening for the E148Q (<a href="#0005">608107.0005</a>), V726A (<a href="#0003">608107.0003</a>), and M694V (<a href="#0001">608107.0001</a>) mutations was performed in 300 Ashkenazi, 101 Iraqi, and 120 Moroccan Jews, with a resulting overall carrier frequency in the 3 ethnic groups, respectively, of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and noncarriers of MEFV mutations was discerned. The frequency of subjects with 2 MEFV mutations who did not express FMF, the so-called phenotype III, was 1 in 300 in Ashkenazi Jews and 1 in 25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40- to 240-fold. These results affirmed the high carrier rate among the Jewish ethnic groups studied in Israel and suggested that most subjects with MEFV mutations are clinically unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="El-Shanti, H., Majeed, H. A., El-Khateeb, M. <strong>Familial Mediterranean fever in Arabs.</strong> Lancet 367: 1016-1024, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16564365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16564365</a>] [<a href="https://doi.org/10.1016/S0140-6736(06)68430-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16564365">El-Shanti et al. (2006)</a> provided a detailed review of the range and distribution of MEFV mutations in the Arab population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16564365" 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="Fragouli, E., Eliopoulos, E., Petraki, E., Sidiropoulos, P., Aksentijevich, I., Galanakis, E., Kritikos, H., Repa, A., Fragiadakis, G., Boumpas, D. T., Goulielmos, G. N. <strong>Familial Mediterranean fever in Crete: a genetic and structural biological approach in a population of 'intermediate risk'.</strong> Clin. Genet. 73: 152-159, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18177465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18177465</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00948.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18177465">Fragouli et al. (2008)</a> studied FMF in native Cretans, analyzing the 12 most frequent MEFV mutations in 71 patients and 158 healthy controls, and found that 59 (83.1%) of 71 FMF patients had at least 1 MEFV mutation, with 5 homozygotes and 54 heterozygotes; no mutations were detected in 16.9% of patients. Population genetic analysis showed an FMF carrier frequency in the healthy Cretan population of approximately 1:17 or about 6%. <a href="#18" class="mim-tip-reference" title="Fragouli, E., Eliopoulos, E., Petraki, E., Sidiropoulos, P., Aksentijevich, I., Galanakis, E., Kritikos, H., Repa, A., Fragiadakis, G., Boumpas, D. T., Goulielmos, G. N. <strong>Familial Mediterranean fever in Crete: a genetic and structural biological approach in a population of 'intermediate risk'.</strong> Clin. Genet. 73: 152-159, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18177465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18177465</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00948.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18177465">Fragouli et al. (2008)</a> noted that this placed the Cretan population in the 'high risk' category in terms of FMF prevalence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18177465" 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 mutational analysis of 376 Lebanese patients with FMF, <a href="#28" class="mim-tip-reference" title="Jalkh, N., Genin, E., Chouery, E., Delague, V., Medlej-Hashim, M., Idrac, C.-A., Megarbane, A., Serre, J.-L. <strong>Familial Mediterranean fever in Lebanon: founder effects for different MEFV mutations.</strong> Ann. Hum. Genet. 72: 41-47, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17711558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17711558</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2007.00386.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17711558">Jalkh et al. (2008)</a> found that the most common mutations were: M694V (28.98%), M694I (12.10%), V726A (19.28%), M680I (5.72%) and E148Q (10.10%). These mutations were estimated to be 7,000, 8,500, 15,000, 23,000, and 30,000 years old, respectively. Varying the mutation rate at 1 of the haplotype markers led to younger age estimates ranging from 3,625 to 18,650 years. A total of 333 different haplotypes were found, 31 of which had a frequency greater than 5% in the whole sample. A comparison of haplotype distributions among religious groups confirmed that Muslim subpopulations, including Shiites and Sunnites, as well as Christians, including Armenians who were formerly settled in the south-eastern part of Asia Minor (Cilicia), were all derived from an ancient common ancestral population, in which most of the MEFV mutations were already present with their respective associated haplotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17711558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Bonyadi, M., Esmaeili, M., Jalali, H., Somi, M. H., Ghaffari, A., Rafeey, M., Sakha, K., Lotfalizadeh, N., Pourhassan, A., Khoshbaten, M., Ardalan, M. R., Laghaeian, N. <strong>MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.</strong> Clin. Genet. 76: 477-480, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863562</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01270.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863562">Bonyadi et al. (2009)</a> tested for 5 common mutations in the MEFV gene (E148Q, M680I, M694V, M694I, and V726A) in 524 unrelated Iranian patients of Azeri Turkish origin with FMF and found their overall frequency to be 52%. Further analysis of 10 less common mutations enabled detection of approximately 9% of the unidentified alleles. The R761H mutation was the most frequently found of the rare alleles (4.7%), and the authors suggested that R761H should be included in routine molecular diagnosis of FMF patients from this ethnic group. Five different complex alleles were identified in 14 patients, including homozygosity for E167D (<a href="#0006">608107.0006</a>)/F479L (<a href="#0008">608107.0008</a>) in 2 patients. <a href="#6" class="mim-tip-reference" title="Bonyadi, M., Esmaeili, M., Jalali, H., Somi, M. H., Ghaffari, A., Rafeey, M., Sakha, K., Lotfalizadeh, N., Pourhassan, A., Khoshbaten, M., Ardalan, M. R., Laghaeian, N. <strong>MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.</strong> Clin. Genet. 76: 477-480, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863562</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01270.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863562">Bonyadi et al. (2009)</a> noted that 43% of presumably mutated alleles remained elusive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19863562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The high allele frequencies for several different pyrin mutations in various populations suggest that the mutant alleles confer a selective advantage. <a href="#42" class="mim-tip-reference" title="Schaner, P., Richards, N., Wadhwa, A., Aksentijevich, I., Kastner, D., Tucker, P., Gumucio, D. <strong>Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states.</strong> Nature Genet. 27: 318-321, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242116</a>] [<a href="https://doi.org/10.1038/85893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242116">Schaner et al. (2001)</a> examined the ret finger protein (rfp) domain (which contains most of the disease-causing mutations) of pyrin during primate evolution. Amino acids that cause human disease are often present as wildtype in other species. This was found to be true at position 653, where a mutation was found for the first time by <a href="#42" class="mim-tip-reference" title="Schaner, P., Richards, N., Wadhwa, A., Aksentijevich, I., Kastner, D., Tucker, P., Gumucio, D. <strong>Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states.</strong> Nature Genet. 27: 318-321, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242116</a>] [<a href="https://doi.org/10.1038/85893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242116">Schaner et al. (2001)</a>, 680, 681, 726, 744, and 761. For several of these human mutations, the mutant represents the reappearance of an ancestral amino acid state. Positive selection can be assessed using the ratio of nonsynonymous substitutions per nonsynonymous site, d(N), to synonymous substitutions per synonymous site, d(S). In theory, a d(N)/d(S) ratio equal to 1.0 indicates neutral change, a d(N)/d(S) ratio less than 1.0 indicates purifying selection, and a d(N)/d(S) ratio greater than 1.0 indicates positive selection. Examination of lineage-specific d(N)/d(S) ratios revealed a pattern consistent with the signature of episodic positive selection. Their data, together with previous human population studies, indicated that selective pressures may have caused functional evolution of pyrin in humans and other primates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242116" 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> rs61752717 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61752717;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/rs61752717?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=rs61752717" 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=rs61752717" 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=RCV000002647 OR RCV000216751 OR RCV000763381 OR RCV001028046 OR RCV001197704 OR RCV001535935 OR RCV002262539 OR RCV002415387 OR RCV002464985 OR RCV003325449 OR RCV003335011 OR RCV005055344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002647, RCV000216751, RCV000763381, RCV001028046, RCV001197704, RCV001535935, RCV002262539, RCV002415387, RCV002464985, RCV003325449, RCV003335011, RCV005055344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002647...</a>
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<p>In a large number of individuals affected with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> identified a 2080A-G transition in the pyrin gene, resulting in a met694-to-val (M694V) substitution. The affected individuals had 4 apparently distinct haplotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288758" 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>The <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> identified this A-G transition in the MEFV gene at nucleotide 1170 of their partial cDNA sequence. They referred to the mutation as the 'MED' variation because it was observed in affected members of families of various origins (Jewish, Armenian, Turkish, Arabian) sharing the MED haplotype. The ethnic diversity indicated that the mutation is ancient and confirms founder effect in the origin of a large fraction of FMF cases in the Mediterranean basin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288094" 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>The MED mutation is found in about 80% of the FMF Jewish (Iraqi and North African) chromosomes. To see if the presence of this mutation could be correlated with particular traits of the disease, <a href="#16" class="mim-tip-reference" title="Dewalle, M., Domingo, C., Rozenbaum, M., Ben-Chetrit, E., Cattan, D., Bernot, A., Dross, C., Dupont, M., Notarnicola, C., Levy, M., Rosner, I., Demaille, J., Touitou, I. <strong>Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF).</strong> Europ. J. Hum. Genet. 6: 95-97, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781020</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781020">Dewalle et al. (1998)</a> examined clinical features in a panel of 109 Jewish FMF patients with 0, 1, or 2 MED mutations. They showed that homozygosity for this mutation was significantly associated with a more severe form of the disease. In homozygous patients, the disease started earlier (mean age 6.4 vs 13.6) and both arthritis and pleuritis were twice as frequent as in patients with one or no M694V mutation. Moreover, all 3 of 3 patients with amyloidosis displayed 2 MED mutations. No association was found with fever, peritonitis, response to colchicine, and erysipeloid eruption. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Cazeneuve, C., Sarkisian, T., Pecheux, C., Dervichian, M., Nedelec, B., Reinert, P., Ayvazyan, A., Kouyoumdjian, J.-C., Ajrapetyan, H., Delpech, M., Goossens, M., Dode, C., Grateau, G., Amselem, S. <strong>MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype--genetic and therapeutic implications.</strong> Am. J. Hum. Genet. 65: 88-97, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364520</a>] [<a href="https://doi.org/10.1086/302459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364520">Cazeneuve et al. (1999)</a> found that the M694V allele had a frequency of 44.8% among 90 Armenian FMF patients from 77 unrelated families. They also found that the homozygous M694V genotype was associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364520" 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="#47" class="mim-tip-reference" title="Yilmaz, E., Ozen, S., Balci, B., Duzova, A., Topaloglu, R., Besbas, N., Saatci, U., Bakkaloglu, A., Ozguc, M. <strong>Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population.</strong> Europ. J. Hum. Genet. 9: 553-555, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11464248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11464248</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11464248">Yilmaz et al. (2001)</a> found that the M694V allele had a frequency of 51.6% among 450 Turkish FMF patients. The carrier frequency in a Turkish population sample of 100 was 3%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11464248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bathelier, C., Lenoir, G., Lucotte, G. <strong>Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients. (Letter)</strong> Genet. Counsel. 21: 461-466, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21290976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21290976</a>]" pmid="21290976">Bathelier et al. (2010)</a> identified the M694V allele in 36 (6%) of 604 French patients with FMF: 7 patients were homozygous for the mutation and 29 were heterozygous. Heterozygosity for the M694V allele was found in 3 of 779 controls, which was significantly lower than among patients. Five of the 604 FMF patients had amyloidosis, and 2 of the patients with amyloidosis were homozygous for the M694V allele. <a href="#3" class="mim-tip-reference" title="Bathelier, C., Lenoir, G., Lucotte, G. <strong>Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients. (Letter)</strong> Genet. Counsel. 21: 461-466, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21290976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21290976</a>]" pmid="21290976">Bathelier et al. (2010)</a> concluded that M694V is a risk allele for the development of amyloidosis in FMF. Among patients carrying the mutant allele, 47% were of North African Jewish ancestry. In addition, the 3 controls who were heterozygous for the mutation were of Sephardic origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21290976" 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 Lebanese female with autosomal recessive FMF, <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> identified compound heterozygous missense mutations in the FMF gene: M694V and S242R (<a href="#0021">608107.0021</a>). Each mutation was inherited from a parent: the unaffected mother carried the S242R variant in heterozygous state, suggesting incomplete penetrance of acute febrile neutrophilic dermatosis (AFND; <a href="/entry/608068">608068</a>). The patient had periodic fevers, serositis, recurrent aphthous ulcers reminiscent of Behcet disease (BD; <a href="/entry/109650">109650</a>), transient skin rashes/nodules, and joint pain that was partially controlled by colchicine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27030597" 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="#26" class="mim-tip-reference" title="Grossman, C., Kassel, Y., Livneh, A., Ben-Zvi, I. <strong>Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation.</strong> Europ. J. Med. Genet. 62: 103532, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30171907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30171907</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30171907">Grossman et al. (2019)</a> compared 57 patients with FMF who were homozygous for the M694V mutation to a cohort of 56 patients with FMF and other MEFV genotypes. They found that the M694V homozygotes had more severe disease, including more attacks per year, higher colchicine dosing, and lower colchicine response compared to the cohort of other genotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30171907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 FAMILIAL MEDITERRANEAN FEVER</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> rs28940578 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940578;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/rs28940578?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=rs28940578" 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=rs28940578" 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=RCV000002648 OR RCV000002664 OR RCV000220431 OR RCV000589706 OR RCV000763380 OR RCV002262540 OR RCV004528066 OR RCV005016225" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002648, RCV000002664, RCV000220431, RCV000589706, RCV000763380, RCV002262540, RCV004528066, RCV005016225" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002648...</a>
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<p>In an Arabian family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), the <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> found that affected members bearing an ARA2 haplotype had a 1172G-A transition in their partial MEFV cDNA sequence, resulting in a met694-to-ile (M694I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288094" 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>.0003 FAMILIAL MEDITERRANEAN FEVER</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002649 OR RCV000220654 OR RCV000515437 OR RCV000623003 OR RCV000984975 OR RCV001535867 OR RCV002262541 OR RCV004739280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002649, RCV000220654, RCV000515437, RCV000623003, RCV000984975, RCV001535867, RCV002262541, RCV004739280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002649...</a>
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<p>In a Druze family and in other familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>) patients and carriers with the Druze (D) haplotype, the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> characterized a 2177T-C transition in the MEFV gene, resulting in a val726-to-ala (V726A) amino acid substitution in the protein. In FMF patients with the D haplotype and in patients with an ARM3 haplotype, the <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> likewise found this T-C transition at nucleotide 1267 of their partial cDNA sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9288094+9288758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 FAMILIAL MEDITERRANEAN FEVER</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> rs28940580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940580;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/rs28940580?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=rs28940580" 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=rs28940580" 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=RCV000030179 OR RCV000222364 OR RCV001197705 OR RCV002251932 OR RCV002254152 OR RCV002262586 OR RCV002415433 OR RCV002477026 OR RCV004739312" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030179, RCV000222364, RCV001197705, RCV002251932, RCV002254152, RCV002262586, RCV002415433, RCV002477026, RCV004739312" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030179...</a>
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<p>In the affected offspring of a single Armenian family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), the <a href="#27" class="mim-tip-reference" title="International FMF Consortium. <strong>Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.</strong> Cell 90: 797-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288758</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288758">International FMF Consortium (1997)</a> found homozygosity for a 2040G-C transversion that resulted in a met680-to-ile (M680I) amino acid substitution in the pyrin protein. In Turkish and Armenian FMF patients with the ARM2 haplotype, the <a href="#19" class="mim-tip-reference" title="French FMF Consortium. <strong>A candidate gene for familial Mediterranean fever.</strong> Nature Genet. 17: 25-31, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>] [<a href="https://doi.org/10.1038/ng0997-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288094">French FMF Consortium (1997)</a> likewise found this G-C transversion at nucleotide 1130 of their partial cDNA sequence of the MEFV gene. <a href="#1" class="mim-tip-reference" title="Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L. <strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong> Am. J. Hum. Genet. 64: 949-962, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>] [<a href="https://doi.org/10.1086/302327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090880">Aksentijevich et al. (1999)</a> found that the same amino acid change was produced by a 2040G-A transition; see <a href="#0013">608107.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9288094+9288758+10090880" 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> rs3743930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3743930;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/rs3743930?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=rs3743930" 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=rs3743930" 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=RCV000002651 OR RCV000002664 OR RCV000218652 OR RCV000513398 OR RCV000761446 OR RCV000768024 OR RCV002251861 OR RCV002262542 OR RCV002266255 OR RCV002326658 OR RCV003224086 OR RCV004528067 OR RCV005208118" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002651, RCV000002664, RCV000218652, RCV000513398, RCV000761446, RCV000768024, RCV002251861, RCV002262542, RCV002266255, RCV002326658, RCV003224086, RCV004528067, RCV005208118" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002651...</a>
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<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (FMF; <a href="/entry/249100">249100</a>), has been reclassified based on the findings of <a href="#37" class="mim-tip-reference" title="Medlej-Hashim, M., Salem, N., Chouery, E., Rawashdeh, M., Delague, V., Haffar, M., Mansour, I., Naman, R., Lefranc, G., Loiselet, J., Megarbane, A. <strong>Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. (Letter)</strong> Clin. Genet. 61: 71-73, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11903360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11903360</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.10114.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11903360">Medlej-Hashim et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11903360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a G-to-C transversion in exon 2 of the MEFV gene, resulting in a glu148-to-gln (E148Q) substitution, as a novel mutation among 120 apparently nonfounder FMF chromosomes. The mutation was found on 29 of 120 (24%) of patient chromosomes and on 3 of 131 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" 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="Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L. <strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong> Am. J. Hum. Genet. 64: 949-962, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>] [<a href="https://doi.org/10.1086/302327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090880">Aksentijevich et al. (1999)</a> found that a high gene frequency of this glu148-to-gln (E148Q) recessive mutation and reduced penetrance accounted for the anomalous pattern of inheritance in an Ashkenazi family previously reported by <a href="#49" class="mim-tip-reference" title="Yuval, Y., Hemo-Zisser, M., Zemer, D., Sohar, E., Pras, M. <strong>Dominant inheritance in two families with familial Mediterranean fever (FMF).</strong> Am. J. Med. Genet. 57: 455-457, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677151</a>] [<a href="https://doi.org/10.1002/ajmg.1320570319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7677151">Yuval et al. (1995)</a> as an unusual case of dominantly inherited FMF. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7677151+10090880" 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="#47" class="mim-tip-reference" title="Yilmaz, E., Ozen, S., Balci, B., Duzova, A., Topaloglu, R., Besbas, N., Saatci, U., Bakkaloglu, A., Ozguc, M. <strong>Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population.</strong> Europ. J. Hum. Genet. 9: 553-555, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11464248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11464248</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11464248">Yilmaz et al. (2001)</a> found that the E148Q allele had a frequency of 3.2% among 450 Turkish FMF patients. The carrier frequency in a Turkish population sample of 100 was 12%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11464248" 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="#37" class="mim-tip-reference" title="Medlej-Hashim, M., Salem, N., Chouery, E., Rawashdeh, M., Delague, V., Haffar, M., Mansour, I., Naman, R., Lefranc, G., Loiselet, J., Megarbane, A. <strong>Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. (Letter)</strong> Clin. Genet. 61: 71-73, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11903360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11903360</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.10114.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11903360">Medlej-Hashim et al. (2002)</a> pointed out that E148Q may be a polymorphism. Its role in connection with mutations on the other allele, the MEFV locus, and on a second mutation on the same allele is unclear. Furthermore, the E148V mutation (<a href="#0017">608107.0017</a>), found in 1 Lebanese patient by <a href="#37" class="mim-tip-reference" title="Medlej-Hashim, M., Salem, N., Chouery, E., Rawashdeh, M., Delague, V., Haffar, M., Mansour, I., Naman, R., Lefranc, G., Loiselet, J., Megarbane, A. <strong>Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. (Letter)</strong> Clin. Genet. 61: 71-73, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11903360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11903360</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.10114.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11903360">Medlej-Hashim et al. (2002)</a>, gives the same digestion pattern on Southern blot as does E148Q when AvaI restriction enzyme is used in the RFLP detection method. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11903360" 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="#40" class="mim-tip-reference" title="Otsuka, M., Koga, T., Sumiyoshi, R., Koike, Y., Furukawa, K., Okamoto, M., Endo, Y., Tsuji, S., Takatani, A., Shimizu, T., Igawa, T., Kawashiri, S.-Y., Iwamoto, N., Ichinose, K., Tamai, M., Nakamura, H., Origuchi, T., Daisuke, N., Kawakami, A. <strong>A case of neutrophilic dermatosis with MEFV gene variant and abnormal activation of peripheral blood monocytes: a case report.</strong> Immun. Med. 42: 45-49, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31204589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31204589</a>] [<a href="https://doi.org/10.1080/25785826.2019.1625507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31204589">Otsuka et al. (2019)</a> reported a 32-year-old Japanese man with adult-onset fever, tonsillitis, and skin rash associated with leukocytosis, increased C-reactive protein, increased ferritin, and activation of monocytes. His rash consisted of painless papules and plaques. Skin biopsy showed neutrophilic dermatosis, and he was diagnosed clinically with adult-onset Sweet disease (see <a href="/entry/608068">608068</a>). He showed a favorable response to colchicine and low-dose corticosteroids. Genetic analysis identified a heterozygous E148Q variant in the MEFV gene, which the authors noted is found in about 20% of healthy individuals in Japan. Functional studies of the variant were not performed, but <a href="#40" class="mim-tip-reference" title="Otsuka, M., Koga, T., Sumiyoshi, R., Koike, Y., Furukawa, K., Okamoto, M., Endo, Y., Tsuji, S., Takatani, A., Shimizu, T., Igawa, T., Kawashiri, S.-Y., Iwamoto, N., Ichinose, K., Tamai, M., Nakamura, H., Origuchi, T., Daisuke, N., Kawakami, A. <strong>A case of neutrophilic dermatosis with MEFV gene variant and abnormal activation of peripheral blood monocytes: a case report.</strong> Immun. Med. 42: 45-49, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31204589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31204589</a>] [<a href="https://doi.org/10.1080/25785826.2019.1625507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31204589">Otsuka et al. (2019)</a> suggested that the variant may have contributed to the development of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31204589" 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> rs104895079 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895079;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/rs104895079?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=rs104895079" 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=rs104895079" 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=RCV000002652 OR RCV000587727 OR RCV000588525 OR RCV001262294 OR RCV002262543 OR RCV003230342 OR RCV005016226" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002652, RCV000587727, RCV000588525, RCV001262294, RCV002262543, RCV003230342, RCV005016226" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002652...</a>
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<p><a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a G-to-C transversion in exon 2 of the MEFV gene, resulting in a glu167-to-asp (E167D) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>) chromosomes. The mutation was found in a single Armenian family and in none of 205 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" 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 unrelated Iranian patients of Azeri Turkish origin with FMF <a href="#6" class="mim-tip-reference" title="Bonyadi, M., Esmaeili, M., Jalali, H., Somi, M. H., Ghaffari, A., Rafeey, M., Sakha, K., Lotfalizadeh, N., Pourhassan, A., Khoshbaten, M., Ardalan, M. R., Laghaeian, N. <strong>MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.</strong> Clin. Genet. 76: 477-480, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863562</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01270.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863562">Bonyadi et al. (2009)</a> identified homozygosity for a complex allele involving E167D and F479L (<a href="#0008">608107.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19863562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<strong>.0007 FAMILIAL MEDITERRANEAN FEVER</strong>
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MEFV, THR267ILE
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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> rs104895081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895081;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/rs104895081?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=rs104895081" 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=rs104895081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002653 OR RCV000991330 OR RCV000996177 OR RCV001535446 OR RCV002262544 OR RCV004532273 OR RCV005016227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002653, RCV000991330, RCV000996177, RCV001535446, RCV002262544, RCV004532273, RCV005016227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002653...</a>
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<p><a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a C-to-T transition in exon 2 of the MEFV gene, resulting in a thr267-to-ile (T267I) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>) chromosomes. The mutation was found in a single family of non-Ashkenazi Jewish origin and in none of 205 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 FAMILIAL MEDITERRANEAN FEVER</strong>
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</h4>
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MEFV, PHE479LEU
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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> rs104895083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895083;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/rs104895083?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=rs104895083" 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=rs104895083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002654 OR RCV000508324 OR RCV000587727 OR RCV002262545 OR RCV003230343 OR RCV003466786 OR RCV004771453 OR RCV005016228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002654, RCV000508324, RCV000587727, RCV002262545, RCV003230343, RCV003466786, RCV004771453, RCV005016228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002654...</a>
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<p><a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a C-to-G transversion in exon 5 of the MEFV gene, resulting in a phe479-to-leu (F479L) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>) chromosomes. The mutation was found in a single Armenian family and in none of 205 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" 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>See <a href="#0006">608107.0006</a> and <a href="#6" class="mim-tip-reference" title="Bonyadi, M., Esmaeili, M., Jalali, H., Somi, M. H., Ghaffari, A., Rafeey, M., Sakha, K., Lotfalizadeh, N., Pourhassan, A., Khoshbaten, M., Ardalan, M. R., Laghaeian, N. <strong>MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.</strong> Clin. Genet. 76: 477-480, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863562</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01270.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863562">Bonyadi et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19863562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, 3-BP DEL, ILE692DEL
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</div>
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</span>
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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> rs104895093 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895093;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/rs104895093?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=rs104895093" 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=rs104895093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907890 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907890;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=rs121907890" 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=rs121907890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000083737 OR RCV000487146 OR RCV002262640 OR RCV003460764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000083737, RCV000487146, RCV002262640, RCV003460764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000083737...</a>
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<div>
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<span class="mim-text-font">
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<p>In an Arab family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), <a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed deletion of AAT from 2 adjacent codons (ile692 and met693) in exon 10 of the MEFV gene, resulting in transformation into a single ATG codon after the deletion (ile692del) and conservation of the reading frame. The mutation was not found in any of 198 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 FAMILIAL MEDITERRANEAN FEVER</strong>
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</span>
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</h4>
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MEFV, LYS695ARG
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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> rs104895094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895094;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/rs104895094?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=rs104895094" 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=rs104895094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002656 OR RCV000196026 OR RCV000213470 OR RCV000415431 OR RCV000508192 OR RCV000622573 OR RCV000768021 OR RCV001270033 OR RCV002262546 OR RCV003224087 OR RCV003389035 OR RCV004739281" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002656, RCV000196026, RCV000213470, RCV000415431, RCV000508192, RCV000622573, RCV000768021, RCV001270033, RCV002262546, RCV003224087, RCV003389035, RCV004739281" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002656...</a>
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<span class="mim-text-font">
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<p>In 3 non-Ashkenazi Jewish families and 1 Armenian family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), <a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed an A-to-G transition in exon 10 of the MEFV gene, resulting in a lys695-to-arg (K695R) substitution. The mutation was also found in 1 of 198 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 FAMILIAL MEDITERRANEAN FEVER</strong>
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MEFV, ALA744SER
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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> rs61732874 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61732874;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/rs61732874?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=rs61732874" 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=rs61732874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002657 OR RCV000213702 OR RCV000768020 OR RCV000999738 OR RCV001535864 OR RCV001770031 OR RCV002262547 OR RCV002415388 OR RCV004532274" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002657, RCV000213702, RCV000768020, RCV000999738, RCV001535864, RCV001770031, RCV002262547, RCV002415388, RCV004532274" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002657...</a>
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<p>In an Armenian family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), <a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a G-to-T transversion in exon 10 of the MEFV gene, resulting in an ala744-to-ser (A744S) substitution. The mutation was not found in 198 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 FAMILIAL MEDITERRANEAN FEVER</strong>
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MEFV, ARG761HIS
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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> rs104895097 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895097;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/rs104895097?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=rs104895097" 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=rs104895097" 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=RCV000002658 OR RCV000217233 OR RCV000763379 OR RCV001536101 OR RCV002262548 OR RCV002512683 OR RCV003466787 OR RCV004739282" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002658, RCV000217233, RCV000763379, RCV001536101, RCV002262548, RCV002512683, RCV003466787, RCV004739282" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002658...</a>
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<p>In an Armenian family with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), <a href="#5" class="mim-tip-reference" title="Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others. <strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong> Hum. Molec. Genet. 7: 1317-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668175</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668175">Bernot et al. (1998)</a> observed a G-to-A transition in exon 10 of the MEFV gene, resulting in an arg761-to-his (R761H) substitution. The mutation was not found in 198 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668175" 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 FAMILIAL MEDITERRANEAN FEVER</strong>
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MEFV, MET680ILE, 2040G-A
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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> rs28940580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940580;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/rs28940580?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=rs28940580" 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=rs28940580" 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=RCV000002659 OR RCV000216518 OR RCV001283820 OR RCV002262549 OR RCV004724727 OR RCV005016229" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002659, RCV000216518, RCV001283820, RCV002262549, RCV004724727, RCV005016229" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002659...</a>
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<p><a href="#1" class="mim-tip-reference" title="Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L. <strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong> Am. J. Hum. Genet. 64: 949-962, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>] [<a href="https://doi.org/10.1086/302327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090880">Aksentijevich et al. (1999)</a> described a 2040G-A transition in the MEFV gene in familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>) causing an M680I amino acid substitution. A G-C transversion of the same nucleotide (<a href="#0004">608107.0004</a>) resulted in the same amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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MEFV, PRO369SER
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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> rs11466023 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11466023;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/rs11466023?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=rs11466023" 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=rs11466023" 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=RCV000002660 OR RCV000215679 OR RCV000416092 OR RCV001251298 OR RCV002262550 OR RCV002433442" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002660, RCV000215679, RCV000416092, RCV001251298, RCV002262550, RCV002433442" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002660...</a>
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<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (<a href="/entry/249100">249100</a>), has been reclassified based on the findings of <a href="#4" class="mim-tip-reference" title="Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee, K., Schmitt, C. P., Wilhelmsen, K. C., Evans, J. P. <strong>An informatics approach to analyzing the incidentalome.</strong> Genet. Med. 15: 36-44, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22995991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22995991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22995991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2012.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22995991">Berg et al. (2013)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22995991" 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 FMF (<a href="/entry/249100">249100</a>), <a href="#1" class="mim-tip-reference" title="Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L. <strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong> Am. J. Hum. Genet. 64: 949-962, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>] [<a href="https://doi.org/10.1086/302327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090880">Aksentijevich et al. (1999)</a> found a pro369to-ser (P369S) mutation in exon 3 of the MEFV gene. They noted that 4 of the mutations initially described in MEFV were in exon 10. The mutation was found on the same allele with the E148Q mutation (see <a href="#0005">608107.0005</a>) in 2 patients and without E148Q in 3 other patients, and in 1 of 222 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090880" 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="#4" class="mim-tip-reference" title="Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee, K., Schmitt, C. P., Wilhelmsen, K. C., Evans, J. P. <strong>An informatics approach to analyzing the incidentalome.</strong> Genet. Med. 15: 36-44, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22995991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22995991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22995991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2012.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22995991">Berg et al. (2013)</a> reclassified the P369S mutation as 'considered to imply carrier status' for a recessive disorder. They noted that the P369S and R408Q (<a href="#0015">608107.0015</a>) mutations had been reported in cis as a single allele resulting in a highly variable clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22995991" 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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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MEFV, ARG408GLN
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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> rs11466024 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11466024;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/rs11466024?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=rs11466024" 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=rs11466024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002661 OR RCV000218029 OR RCV000224408 OR RCV001251298 OR RCV002262551 OR RCV002362552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002661, RCV000218029, RCV000224408, RCV001251298, RCV002262551, RCV002362552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002661...</a>
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<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (<a href="/entry/249100">249100</a>), has been reclassified based on the findings of <a href="#4" class="mim-tip-reference" title="Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee, K., Schmitt, C. P., Wilhelmsen, K. C., Evans, J. P. <strong>An informatics approach to analyzing the incidentalome.</strong> Genet. Med. 15: 36-44, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22995991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22995991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22995991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2012.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22995991">Berg et al. (2013)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22995991" 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 genotypic study of 90 Armenian FMF (<a href="/entry/249100">249100</a>) patients from 77 unrelated families, <a href="#10" class="mim-tip-reference" title="Cazeneuve, C., Sarkisian, T., Pecheux, C., Dervichian, M., Nedelec, B., Reinert, P., Ayvazyan, A., Kouyoumdjian, J.-C., Ajrapetyan, H., Delpech, M., Goossens, M., Dode, C., Grateau, G., Amselem, S. <strong>MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype--genetic and therapeutic implications.</strong> Am. J. Hum. Genet. 65: 88-97, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364520</a>] [<a href="https://doi.org/10.1086/302459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364520">Cazeneuve et al. (1999)</a> identified a novel mutation, arg408-to-gln (R408Q) in the MEFV gene. The mutation was identified in 1 patient in cis with the E148Q (<a href="#0005">608107.0005</a>) and P369S (<a href="#0014">608107.0014</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364520" 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="#4" class="mim-tip-reference" title="Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee, K., Schmitt, C. P., Wilhelmsen, K. C., Evans, J. P. <strong>An informatics approach to analyzing the incidentalome.</strong> Genet. Med. 15: 36-44, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22995991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22995991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22995991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2012.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22995991">Berg et al. (2013)</a> reclassified the R408Q mutation as 'considered to imply carrier status' for a recessive disorder. They noted that the R408Q and P369S (<a href="#0014">608107.0014</a>) mutations had been reported in cis as a single allele resulting in a highly variable clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22995991" 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>.0016 FAMILIAL MEDITERRANEAN FEVER</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> rs104895085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895085;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/rs104895085?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=rs104895085" 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=rs104895085" 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=RCV000002662 OR RCV000255083 OR RCV003466788 OR RCV005016230" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002662, RCV000255083, RCV003466788, RCV005016230" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002662...</a>
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<p>In the study of the evolution of pyrin in primates, <a href="#42" class="mim-tip-reference" title="Schaner, P., Richards, N., Wadhwa, A., Aksentijevich, I., Kastner, D., Tucker, P., Gumucio, D. <strong>Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states.</strong> Nature Genet. 27: 318-321, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242116</a>] [<a href="https://doi.org/10.1038/85893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242116">Schaner et al. (2001)</a> reported a 1958G-A transition in the MEFV gene that resulted in an arg653-to-his (R653H) change. They pointed out that the human wildtype amino acid, arginine, is seen only in gorilla, chimp, and human. All other species (except dwarf lemur) contain histidine at this position. Thus, histidine is most likely the ancestral amino acid, and the human disease mutation from arginine to histidine replicates this ancestral (and highly conserved) state. A similar kind of pattern was seen in the evolutionary history of other codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242116" 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> rs104895076 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895076;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/rs104895076?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=rs104895076" 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=rs104895076" 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=RCV000002663 OR RCV000216721 OR RCV000415966 OR RCV002262552 OR RCV002482818 OR RCV003125825 OR RCV003125826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002663, RCV000216721, RCV000415966, RCV002262552, RCV002482818, RCV003125825, RCV003125826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002663...</a>
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<p><a href="#37" class="mim-tip-reference" title="Medlej-Hashim, M., Salem, N., Chouery, E., Rawashdeh, M., Delague, V., Haffar, M., Mansour, I., Naman, R., Lefranc, G., Loiselet, J., Megarbane, A. <strong>Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. (Letter)</strong> Clin. Genet. 61: 71-73, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11903360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11903360</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.10114.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11903360">Medlej-Hashim et al. (2002)</a> described the glu148-to-val mutation (E148V) in 1 Lebanese patient with familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>). They pointed out that the usual RFLP detection method used for E148Q (<a href="#0005">608107.0005</a>), which may represent a polymorphism or at the most a weakly pathogenic allele, gives the same restriction pattern as does E148V. When AvaI restriction enzyme is used the 2 mutations cause the same pattern; different patterns are created by E148Q and E148V when MvaI enzyme is used. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11903360" 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>.0018 FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002648 OR RCV000002651 OR RCV000002664 OR RCV000218652 OR RCV000220431 OR RCV000513398 OR RCV000589706 OR RCV000761446 OR RCV000763380 OR RCV000768024 OR RCV002251861 OR RCV002262540 OR RCV002262542 OR RCV002266255 OR RCV002326658 OR RCV003224086 OR RCV004528066 OR RCV004528067 OR RCV005016225 OR RCV005208118" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002648, RCV000002651, RCV000002664, RCV000218652, RCV000220431, RCV000513398, RCV000589706, RCV000761446, RCV000763380, RCV000768024, RCV002251861, RCV002262540, RCV002262542, RCV002266255, RCV002326658, RCV003224086, RCV004528066, RCV004528067, RCV005016225, RCV005208118" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002648...</a>
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<p>In affected members of 2 unrelated families with autosomal dominant FMF (<a href="/entry/134610">134610</a>), <a href="#8" class="mim-tip-reference" title="Booth, D. R., Gillmore, J. D., Lachmann, H. J., Booth, S. E., Bybee, A., Soyturk, M., Akar, S., Pepys, M. B., Tunca, M., Hawkins, P. N. <strong>The genetic basis of autosomal dominant familial Mediterranean fever.</strong> Quart. J. Med. 93: 217-221, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10787449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10787449</a>] [<a href="https://doi.org/10.1093/qjmed/93.4.217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10787449">Booth et al. (2000)</a> identified 2 mutations in the MEFV gene on the same allele: a glu148-to-gln (E148Q) substitution and a met694-to-ile (M694I; <a href="#0002">608107.0002</a>) substitution. One family was Turkish and the other Indian. Complete sequencing of the MEFV gene failed to identify mutations on the second allele. Several asymptomatic individuals from both families carried the mutation, indicating disease penetrance of 50 to 90%. The clinical features of FMF in these families were classical in every respect, including favorable response to colchicine; however, no patients developed amyloidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10787449" 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>.0019 FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT</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> rs104895091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895091;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/rs104895091?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=rs104895091" 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=rs104895091" 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=RCV000002665 OR RCV000083740 OR RCV000757455" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002665, RCV000083740, RCV000757455" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002665...</a>
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<p>In affected members of 3 unrelated British families with autosomal dominant FMF (<a href="/entry/134610">134610</a>), <a href="#8" class="mim-tip-reference" title="Booth, D. R., Gillmore, J. D., Lachmann, H. J., Booth, S. E., Bybee, A., Soyturk, M., Akar, S., Pepys, M. B., Tunca, M., Hawkins, P. N. <strong>The genetic basis of autosomal dominant familial Mediterranean fever.</strong> Quart. J. Med. 93: 217-221, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10787449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10787449</a>] [<a href="https://doi.org/10.1093/qjmed/93.4.217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10787449">Booth et al. (2000)</a> identified heterozygosity for a 3-bp deletion in the MEFV gene, resulting in deletion of residue met694. This codon is the site of 2 other common mutations in the MEFV gene (M694V; <a href="#0001">608107.0001</a> and M694I; <a href="#0002">608107.0002</a>). The clinical features of FMF in these families were classical in every respect, including favorable response to colchicine. Incomplete penetrance was observed. Only 1 patient had amyloidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10787449" 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">rs104895105 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895105;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=rs104895105" 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=rs104895105" 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=RCV000002666 OR RCV000083696 OR RCV001562614 OR RCV003125827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002666, RCV000083696, RCV001562614, RCV003125827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002666...</a>
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<p>In affected members of a Spanish kindred with autosomal dominant FMF (<a href="/entry/134610">134610</a>), <a href="#2" class="mim-tip-reference" title="Aldea, A., Campistol, J. M., Arostegui, J. I., Rius, J., Maso, M., Vives, J., Yague, J. <strong>A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?</strong> Am. J. Med. Genet. 124A: 67-73, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14679589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14679589</a>] [<a href="https://doi.org/10.1002/ajmg.a.20296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14679589">Aldea et al. (2004)</a> identified a heterozygous 1432C-T transition in exon 5 of the MEFV gene, resulting in a his478-to-tyr (H478Y) substitution in the coiled-coil domain of the protein. No additional mutations were detected in the MEFV gene or in the TNFRSF1A gene (<a href="/entry/191190">191190</a>). Affected individuals showed a severe form of the disorder, with renal amyloidosis developing in the older patients. Although there was no response to colchicine, patients did show favorable response to monoclonal antibodies against TNF-alpha (TNFA; <a href="/entry/191160">191160</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14679589" 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>.0021 NEUTROPHILIC DERMATOSIS, ACUTE FEBRILE</strong>
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FAMILIAL MEDITERRANEAN FEVER, INCLUDED
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MEFV, SER242ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895127;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs104895127</a>)
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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> rs104895127 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104895127;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/rs104895127?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=rs104895127" 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=rs104895127" 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=RCV000083793 OR RCV001172095 OR RCV001174523 OR RCV005016371" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000083793, RCV001172095, RCV001174523, RCV005016371" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000083793...</a>
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<p><strong><em>Acute Febrile Neutrophilic Dermatosis</em></strong></p><p>
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In 12 affected members of a large 3-generation Belgian family with acute febrile neutrophilic dermatosis (AFND; <a href="/entry/608068">608068</a>), <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> identified a heterozygous c.726C-G transversion in exon 2 of the MEFV gene, resulting in a ser242-to-arg (S242R) substitution at a conserved residue in mammals. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was seen in 1 of 122,836 chromosomes in the ExAC database, in a Colombian male for whom clinical information was not available (1000 Genomes Project database). The same heterozygous S242R mutation was subsequently identified in 2 additional pedigrees (A and C) with an overlapping phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation enhanced the formation of apoptosis-associated speck-like proteins compared to controls. Downstream of ASC, the S242R mutation resulted in activation of CASP1 (<a href="/entry/147678">147678</a>), as well as increased secretion of IL1B compared to wildtype. Further studies showed that the mutation impaired phosphorylation of S242, which resulted in removal of inhibitory 14-3-3 proteins (see, e.g., <a href="/entry/609009">609009</a> and <a href="/entry/605066">605066</a>) and constitutive activation of pyrin. One patient was successfully treated with anakinra, which blocks IL1B. <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> noted that the molecular mechanism resulting from the S242R mutation differed from that of FMF-associated mutations M694V, M680I, and V726A, which had no appreciable effect on 14-3-3 binding. Of note, the carrier mother in family C did not have neutrophilic dermatosis, but she did have some features of the disorder, including recurrent fevers and elevated acute-phase reactants. These findings suggested incomplete penetrance or clinical variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27030597" 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>Familial Mediterranean Fever, Autosomal Recessive</em></strong></p><p>
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In a Lebanese female (family B) with autosomal recessive familial Mediterranean fever (FMF; <a href="/entry/249100">249100</a>), <a href="#35" class="mim-tip-reference" title="Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry D A., Lawless, D., De Nardo, D., Grcia-Perez, J. E., Dagley L. F., Holley, C. L., Dooley, J., and 20 others. <strong>Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.</strong> Sci. Transl. Med. 8: 332ra45, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27030597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27030597</a>] [<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27030597">Masters et al. (2016)</a> identified compound heterozygous missense mutations in the FMF gene: M694V (<a href="#0001">608107.0001</a>) and S242R. Each mutation was inherited from a parent: the unaffected mother carried the S242R variant in heterozygous state, suggesting incomplete penetrance of AFND. The patient had periodic fevers, serositis, recurrent aphthous ulcers reminiscent of Behcet disease (BD; <a href="/entry/109650">109650</a>), transient skin rashes/nodules, and joint pain that was partially controlled by colchicine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27030597" 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="#29" class="mim-tip-reference" title="Kiyota, M., Oya, M., Ayano, M., Niiro, H., Iwasaki, T., Fujiwara, M., Oda, Y., Fujimoto, K., Ida, H. <strong>First case of pyrin-associated autoinflammation with neutrophilic dermatosis complicated by amyloidosis. (Letter)</strong> Rheumatology 59: e41-e43, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31998953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31998953</a>] [<a href="https://doi.org/10.1093/rheumatology/keaa005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31998953">Kiyota et al. (2020)</a> reported a 45-year-old Japanese man with a systemic autoinflammatory disorder with intermittent fever and amyloidosis, consistent with FMF, as well as pustular dermatosis with neutrophilic aggregates since childhood. The authors noted that he had abdominal symptoms, rather than classic serositis, and that the skin problems had been the main symptom since chilhood, suggesting a phenotype that overlapped with AFND (<a href="/entry/608068">608068</a>). Genetic analysis identified compound heterozygous missense variants in the MEFV gene (S242R and E148Q, <a href="#0005">608107.0005</a>). His unaffected mother was heterozygous for the S242R mutation, indicating incomplete penetrance of AFND. Functional studies of the variants were not performed, but the authors suggested that the E148Q polymorphism may act as a disease modifier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31998953" 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>.0022 NEUTROPHILIC DERMATOSIS, ACUTE FEBRILE</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">rs1959081392 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1959081392;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=rs1959081392" 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=rs1959081392" 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=RCV001174525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001174525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001174525</a>
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<p>In 3 affected members of a Spanish family with acute febrile neutrophilic dermatosis (AFND; <a href="/entry/608068">608068</a>), <a href="#38" class="mim-tip-reference" title="Moghaddas, F., Llamas, R., De Nardo, D., Martinez-Banaclocha, H., Martinez-Garcia, J. J. Mesa-del-Castillo, P., Baker, P. J., Gargallo, V., Mensa-Vilaro, A., Canna, S., Wicks, I. P., Pelegrin, P., Arostegui, J. I., Masters, S. L. <strong>A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to familial Mediterranean fever.</strong> Ann. Rheum. Dis. 76: 2085-2094, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28835462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28835462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28835462[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/annrheumdis-2017-211473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28835462">Moghaddas et al. (2017)</a> identified a heterozygous c.730G-A transition in exon 2 of the MEFV gene, resulting in a glu244-to-lys (E244K) substitution at a highly conserved residue. The mutation, which was found by direct sequencing of exon 2 of the MEFV gene, was not found in the 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in 250 healthy Spanish controls. Patient-derived monocytes transfected with the mutation showed augmented ASC (<a href="/entry/606838">606838</a>) speck formation both at baseline and upon LPS exposure, increased CASP1 activity, increased IL1B and IL18, and increased inflammatory cell death compared to controls. These findings were associated with reduced phosphorylation of the MEFV 14-3-3 binding motif and reduced 14-3-3 binding compared to controls, ultimately resulting in inappropriate activation of MEFV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28835462" 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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Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L.
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<strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong>
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Am. J. Hum. Genet. 64: 949-962, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302327" target="_blank">Full Text</a>]
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Aldea, A., Campistol, J. M., Arostegui, J. I., Rius, J., Maso, M., Vives, J., Yague, J.
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<strong>A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?</strong>
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Am. J. Med. Genet. 124A: 67-73, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14679589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14679589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14679589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20296" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/gim.2012.112" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.8.1317" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01270.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3109/13506129809007299" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/qjmed/93.4.217" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0002-9297(07)62944-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302459" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s003350010082" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(03)00056-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0602081103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<456::AID-HUMU6>3.0.CO;2-G" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(06)68430-4" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288094</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0997-25" target="_blank">Full Text</a>]
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<strong>The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5200776" target="_blank">Full Text</a>]
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<strong>The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.</strong>
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[<a href="https://doi.org/10.1002/art.10944" target="_blank">Full Text</a>]
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<strong>Familial Mediterranean fever: prevalence, penetrance and genetic drift.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5200672" target="_blank">Full Text</a>]
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<strong>Familial Mediterranean fever: The segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability.</strong>
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[<a href="https://doi.org/10.1002/ajmg.10352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2006.04.185" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp437" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2018.08.013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80539-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.2007.00386.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/rheumatology/keaa005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1438" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200608" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200574" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/scitranslmed.aaf1471" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200725" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2002.10114.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/annrheumdis-2017-211473" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35056009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1080/25785826.2019.1625507" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.20.3001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/85893" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30457980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30457980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30457980[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30457980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI121372" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.2135380100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature13449" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200674" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2007.08.029" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320570319" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/03/2021
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/10/2020<br>Cassandra L. Kniffin - updated : 06/09/2020<br>Bao Lige - updated : 03/13/2019<br>Ada Hamosh - updated : 10/22/2014<br>Ada Hamosh - updated : 5/31/2013<br>Cassandra L. Kniffin - updated : 3/5/2013<br>George E. Tiller - updated : 11/1/2010<br>Marla J. F. O'Neill - updated : 1/13/2010<br>Cassandra L. Kniffin - updated : 10/15/2008<br>Marla J. F. O'Neill - updated : 7/10/2008<br>Patricia A. Hartz - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/22/2007<br>Paul J. Converse - updated : 8/16/2006<br>Cassandra L. Kniffin - updated : 3/15/2006<br>Cassandra L. Kniffin - updated : 6/23/2004
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Creation Date:
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Cassandra L. Kniffin : 9/22/2003
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carol : 07/28/2023
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mgross : 05/10/2021<br>mgross : 03/03/2021<br>carol : 08/11/2020<br>carol : 08/10/2020<br>carol : 06/15/2020<br>carol : 06/12/2020<br>ckniffin : 06/09/2020<br>carol : 02/20/2020<br>carol : 05/17/2019<br>carol : 03/14/2019<br>mgross : 03/13/2019<br>carol : 03/12/2019<br>alopez : 11/14/2016<br>alopez : 11/14/2016<br>joanna : 07/01/2016<br>alopez : 10/22/2014<br>carol : 10/22/2014<br>alopez : 5/31/2013<br>carol : 3/7/2013<br>ckniffin : 3/5/2013<br>alopez : 11/3/2010<br>terry : 11/1/2010<br>carol : 2/17/2010<br>wwang : 1/26/2010<br>terry : 1/13/2010<br>wwang : 6/15/2009<br>terry : 6/3/2009<br>wwang : 10/17/2008<br>ckniffin : 10/15/2008<br>wwang : 7/11/2008<br>terry : 7/10/2008<br>mgross : 11/29/2007<br>mgross : 11/29/2007<br>wwang : 10/22/2007<br>mgross : 8/25/2006<br>terry : 8/16/2006<br>wwang : 3/29/2006<br>ckniffin : 3/15/2006<br>tkritzer : 6/30/2004<br>ckniffin : 6/23/2004<br>carol : 5/4/2004<br>carol : 9/30/2003<br>ckniffin : 9/23/2003
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<span class="mim-font">
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<strong>*</strong> 608107
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MEFV INNATE IMMUNITY REGULATOR, PYRIN; MEFV
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<em>Alternative titles; symbols</em>
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FAMILIAL MEDITERRANEAN FEVER GENE<br />
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PYRIN<br />
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MARENOSTRIN
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MEFV</em></strong>
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<strong>SNOMEDCT:</strong> 12579009, 84625002;
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<strong>ICD10CM:</strong> L98.2, M04.1;
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<strong>ICD9CM:</strong> 277.31;
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:3,242,027-3,256,633 </span>
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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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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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16p13.3
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Familial Mediterranean fever, AD
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<span class="mim-font">
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134610
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Autosomal dominant
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3
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Familial Mediterranean fever, AR
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<span class="mim-font">
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249100
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Autosomal recessive
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3
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Neutrophilic dermatosis, acute febrile
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608068
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The MEFV gene encodes pyrin, which functions as an innate immune sensor that can trigger formation of an inflammasome, allowing the production of inflammatory mediators during infection (summary by Masters et al., 2016). </p>
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<strong>Cloning and Expression</strong>
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<p>By positional cloning, the International FMF Consortium (1997) identified a gene from a 115-kb familial Mediterranean fever (249100) candidate interval on chromosome 16p. The novel gene encoded a 3.7-kb transcript that was expressed almost exclusively in mature granulocytes. The predicted 781-amino acid protein, which they termed pyrin, is a member of a family of nuclear factors homologous to the Ro52 antigen (109092) and the RET finger protein (RFP; 602165). Northern blot analysis showed expression in peripheral blood, but there was no significant expression in 14 other normal tissues, including spleen, thymus, and lymph nodes. </p><p>Simultaneously and independently, the French FMF Consortium (1997) identified transcriptional units in a critical MEFV interval of 60 kb on the basis of genomic sequence analysis and exon trapping. They identified 4 genes, one of which encoded pyrin, which this consortium designated marenostrin (from the Latin name of the Mediterranean Sea, mare nostrum). The C terminus of the deduced protein showed similarities to those of RET finger protein and butyrophilin (601610). </p><p>Papin et al. (2000) described the isolation and expression of a novel human MEFV isoform, MEFV-d2, generated by in-frame alternative splicing of exon 2. This transcript, expressed in leukocytes, predicts a 570-residue protein designated marenostrin-d2. Unlike the full-length protein (marenostrin-fl), which is distributed homogeneously over the entire cytoplasm, marenostrin-d2 concentrates into the nucleus. Deletion of the putative nuclear localization signals did not alter the nuclear localization of marenostrin-d2, whereas deletion of the domain encoded by the exon 1-exon 3 splice junction disrupted this localization. The authors hypothesized that MEFV encodes a nuclear protein and that MEFV alternative splicing may control functions of wildtype and mutant marenostrin proteins by regulating their translocation to the nucleus. Mansfield et al. (2001) reported results of studies of the subcellular localization of wildtype pyrin that did not support the proposed nuclear or Golgi localization. They demonstrated colocalization with microtubules. </p><p>Goulielmos et al. (2006) reported that the human pyrin protein contains several conserved domains, including an N-terminal pyrin domain (PYD), followed by a bZIP transcription factor basic domain, a B-box zinc finger coiled-coil domain, and a C-terminal PRYSPRY domain. The B-box zinc finger coiled-coil domain is involved in homo- or heterodimer formation, and the PRYSPRY domain is involved in protein-protein interactions. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By positional cloning, the International FMF Consortium (1997) identified the MEFV gene on chromosome 16p. Chae et al. (2000) localized the mouse Mefv gene to chromosome 16, region A3-B1, thus extending a region of syntenic homology with human 16p13.3. </p>
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<strong>Gene Function</strong>
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<p>Centola et al. (2000) presented data placing the MEFV gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an interferon-gamma immediate early gene. </p><p>Mansfield et al. (2001) demonstrated colocalization of wildtype pyrin with microtubules. Deletion constructs showed that the unique N-terminal domain of pyrin is necessary and sufficient for the colocalization of pyrin with microtubules. By phalloidin staining, colocalization of pyrin with actin was also observed in perinuclear filaments and in peripheral lamellar ruffles. The authors proposed that pyrin regulates inflammatory responses at the level of leukocyte cytoskeletal organization and that the unique therapeutic effect of colchicine in FMF may be dependent on this interaction. </p><p>To study the physiologic role of pyrin, Chae et al. (2003) generated mice expressing a truncated pyrin molecule that, similar to FMF patients, retained the full PYRIN domain. Bacterial lipopolysaccharide (LPS) induced accentuated body temperatures and increased lethality in homozygous mutant mice. When stimulated, macrophages from these mice produced increased amounts of activated caspase-1 and, consequently, elevated levels of mature Il1b. Full-length pyrin competed in vitro with caspase-1 for binding to Asc (606838), a caspase-1 activator. Apoptosis was impaired in macrophages from pyrin-truncation mice through an IL1-independent pathway. These results supported a critical role for pyrin in the innate immune response, possibly by acting on ASC, and suggested a biologic basis for the selection of hypomorphic pyrin variants in man. </p><p>Using a yeast 2-hybrid assay, Shoham et al. (2003) showed that human pyrin and human PSTPIP1 (606347) interacted with each other and colocalized within peripheral blood granulocytes and monocytes. Tyrosine phosphorylation of PSTPIP1 markedly increased binding to pyrin. Expression of 2 PSTPIP1 mutations (606347.0001 and 606347.0002) associated with PAPA syndrome (604416) resulted in increased PSTPIP1-pyrin binding. Shoham et al. (2003) suggested that sequestration of pyrin in PAPA syndrome may prevent pyrin's normal immunoregulatory functions, resulting in an excess of IL1-beta production, as found in a patient with PAPA syndrome. The findings elucidated another pathway involved in regulating inflammation, and linked PAPA syndrome and familial Mediterranean fever as disorders arising from defects within the same pathway. </p><p>By coimmunoprecipitation analysis, Chae et al. (2006) demonstrated direct interaction between pyrin and caspase-1 (CASP1; 147678) that was independent of ASC. Mutation analysis showed that the C-terminal B30.2 domain of pyrin was necessary and sufficient for binding with CASP1. Constructs of the B30.2 domain of wildtype pyrin, but not constructs harboring FMF-associated mutations in the B30.2 domain (i.e., M694V; 608107.0001), bound CASP1 strongly and inhibited IL1B (147720) secretion. Knockdown of pyrin in THP-1 cells by MEFV small interfering RNA caused increased IL1B secretion in response to lipopolysaccharide. Computational modeling confirmed the interaction between the p10 and p20 subunits of CASP1 and pyrin B30.2. Treatment of a patient refractory to colchicine and homozygous for M694V with anakinra, a recombinant IL1R antagonist (IL1RN; 147679), controlled serum amyloid A (SAA1; 104750) and C-reactive protein (CRP; 123260) levels. Chae et al. (2006) concluded that wildtype pyrin inhibits CASP1 activation. They proposed that FMF-associated mutations have less of an inhibitory effect on CASP1 activation and may have been selected in human history because of the resulting increase in innate immunity. </p><p>Yu et al. (2007) found that both pyrin and PSTPIP1 formed homotrimers, and that the pyrin homotrimer was inactive due to masking of its PYD motif by its B box. PSTPIP1 activated pyrin by binding to its B box and unmasking the PYD, leading to interaction of the PYD with ASC, ASC dimerization, and recruitment and activation of caspase-1. Autoinflammatory PSTPIP1 mutants had higher binding affinities for the pyrin B box than did wildtype PSTPIP1. </p><p>Grandemange et al. (2009) examined the effect of indirect and direct inhibition of nonsense-mediated decay (NMD) on expression of the MEFV transcripts in THP1, monocyte, and neutrophil cells. MEFV was regulated by NMD in both a cell- and transcript-specific manner. The authors suggested the possibility of translation of alternatively spliced MEFV transcripts into several pyrin variants according to cell type and inflammatory state. </p><p>Xu et al. (2014) showed that pyrin mediates CASP1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. Xu et al. (2014) further demonstrated that Burkholderia cenocepacia inactivates RHOA (165390) by deamidating asparagine-41, also in the switch-I region, and thereby triggers pyrin inflammasome activation, both of which require the bacterial type VI secretion system. Loss of the pyrin inflammasome causes elevated intramacrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Xu et al. (2014) concluded that pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a paradigm in mammalian innate immunity. </p><p>Sharma et al. (2019) found that Tnf (191160) signaling promoted pyrin expression and inflammasome activation in response to multiple stimuli in mice. </p><p>Magupalli et al. (2020) showed that NLRP3 (606416)- and pyrin-mediated inflammasome assembly, caspase activation, and IL1-beta conversion occurred at the microtubule-organizing center (MTOC) in mouse and human cells. HDAC6 (300272) was required for microtubule transport and assembly of these inflammasomes both in vitro and in mice. The authors noted that because HDAC6 can transport ubiquitinated pathologic aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for downregulation of these inflammasomes by autophagy. </p>
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Goulielmos et al. (2006) constructed a 3-dimensional model of the PRYSPRY domain of pyrin. The core of the PRYSPRY domain consists of a 5-strand and 7-strand beta sandwich that is surrounded by linking loops. A hydrophobic binding cavity is formed by 1 external side of the beta sandwich and several loops. The authors localized the most frequent pyrin mutations in MEFV to the PRYSPRY domain model and classified them according to disease severity. </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>Familial Mediterranean Fever, Autosomal Recessive</em></strong></p><p>
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By screening 165 individuals from 65 families with familial Mediterranean fever, the International FMF Consortium (1997) identified 3 different missense mutations in exon 10 of the MEFV gene (608107.0001, 608107.0003, 608107.0004) that accounted for 78 carrier chromosomes. The authors noted that none of the identified mutations resulted in a truncated protein, and they suggested that the periodic nature of inflammatory attacks in FMF is consistent with a protein that functions adequately at steady state but decompensates under stress. The French FMF Consortium (1997) identified 4 sequence variations (608107.0001-608107.0004) in the marenostrin gene that correlated with FMF in various ethnic groups. In 72% of the patients in their sample, 1 or 2 of the 4 mutations were found. </p><p>Gershoni-Baruch et al. (2002) reported a family in which 4 different MEFV mutations were segregating: V726A (608107.0003), M694V (608107.0001), M680I (608107.0004), and K695R (608107.0010). Three parents and 1 grandparent who each carried 2 mutated alleles remained asymptomatic. Of 9 grandchildren who were compound heterozygotes for 2 mutations in the MEFV gene, only those with either the M694V/V726A or the M694V/M680I genotypes manifested the disease, bearing evidence of the severity of M694V in individuals sharing a similar genetic and environmental background. Nevertheless, 1 father and 1 grandmother who carried the M694V/V726A compound heterozygous genotype were symptom-free, while 4 grandchildren of the same genotype manifested the disease from an early age, suggesting a role of additional environmental and genetic modifiers. The occurrence of 4 different mutations in 2 sets of consanguineous parents was a remarkable finding. </p><p><strong><em>Acute Febrile Neutrophilic Dermatosis</em></strong></p><p>
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In 12 affected members of a large 3-generation Belgian family with acute febrile neutrophilic dermatosis (AFND; 608068), Masters et al. (2016) identified a heterozygous missense mutation in exon 2 of the MEFV gene (S242R; 608107.0021). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous S242R mutation was subsequently identified in 3 additional pedigrees with an overlapping phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation enhanced the formation of ASC (PYCARD; 606838) compared to controls. Downstream of ASC, the S242R mutations resulted in activation of CASP1 (147678) as well as increased secretion of IL1B compared to wildtype. Further studies showed that the mutation impaired phosphorylation of S242, which resulted in removal of inhibitory 14-3-3 proteins (see, e.g., 609009 and 605066) and constitutive activation of pyrin. One patient was successfully treated with anakinra, which blocks IL1RA. Masters et al. (2016) noted that the molecular mechanism resulting from the S242R mutation differed from that of FMF-associated mutations M694V, M680I, and V726A, which had no appreciable effect on 14-3-3 binding. </p><p>In 3 affected members of a Spanish family with AFND, Moghaddas et al. (2017) identified a heterozygous missense mutation in exon 2 of the MEFV gene (E244K; 608107.0022). The mutation, which was found by direct sequencing of the MEFV gene, was not found in the 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in 250 healthy Spanish controls. Patient-derived monocytes and cells transfected with the mutation showed augmented ASC speck formation both at baseline and upon LPS exposure, increased CASP1 activity, increased IL1B and IL18, and increased inflammatory cell death compared to controls, consistent with activation of the inflammasome. These findings were associated with reduced phosphorylation of the MEFV 14-3-3 binding motif and reduced 14-3-3 binding compared to controls, ultimately resulting in inappropriate activation of MEFV. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<p>The International FMF Consortium (1997) suggested that phenotypic differences may be related to different mutations. The M694V mutation (608107.0001) was frequent in populations with a higher incidence of systemic amyloidosis, whereas the V726A mutation (608107.0003) was found in a population in which amyloidosis is less common. They also suggested that a heterozygous selective advantage based on heightened inflammatory response to some pathogen or class of pathogens endemic in the Mediterranean may be responsible for the high gene frequencies for FMF in populations in that area. </p><p>Livneh et al. (2001) studied 8 patients with FMF who also had Behcet disease (BD; 109650). Sequence analysis of the MEFV gene revealed that all 8 patients had only a single mutated allele. The patients' noncarrier chromosomes converged into 3 different MEFV haplotypes and were shared by unaffected heterozygous family members. The findings did not support a role for the noncarrier chromosome in the induction of FMF, and suggested that Behcet disease may induce the expression of FMF in carriers, despite the known recessive mode of inheritance. In the 8 families studied, Behcet disease was found in 10 of 11 heterozygous FMF patients versus 1 of 16 heterozygous unaffected individuals (P less than 0.001). Livneh et al. (2001) hypothesized that a reduced level of functional pyrin, presumably characterizing heterozygosity, and an increased demand for pyrin by activated granulocytes of Behcet disease, may ultimately lead to FMF attacks. The authors also noted the possibility that not all patients with FMF conform to a recessive mode of inheritance, and that Behcet disease may be only one example of various inflammatory, infectious, and other stimuli predisposing carriers of a mutated MEFV gene to acute attacks of FMF. </p><p>Touitou (2001) reviewed the spectrum of MEFV mutations reported in FMF. Of the 29 known mutations, 26 were missense mutations, 2 were small deletions, and 1 was a nonsense mutation. Three apparent mutation hotspots were identified at codons 148, 680, and 694. Five frequent founder mutations accounted for the majority (74%) of mutations, whereas the other 24 known mutations were found in no more than 1% of FMF chromosomes. About a quarter of all FMF alleles were unidentified. The M694V mutation (608107.0001) was the most frequent mutation in the commonly affected populations of Arabs, Armenians, non-Ashkenazi Jews, and Turks, ranging from 20 to 65% of FMF chromosomes. The penetrance of M694V homozygosity was very high (99%) and correlated with a severe disease course with frequent amyloidosis, early disease onset, and arthritis. In contrast, the E148Q mutation (608107.0005) was the least penetrant, with 55% asymptomatic cases at homozygosity. Amyloidosis had never been reported in those patients. The author concluded that the overall FMF phenotype is likely to be influenced by other genetic as well as nongenetic factors. </p><p>Medlej-Hashim et al. (2001) attempted a genotype-phenotype correlation in FMF. They studied 147 unrelated Lebanese and Jordanian FMF patients and correlated IgD plasma level with specific phenotypic characteristics. The IgD plasma distribution in patients was similar to that of healthy subjects, which was not in favor of a direct effect of MEFV mutations on serum IgD levels. However, homozygote status for the M694V mutation (odds ratio, 6.25) and to a lesser extent V726A (OR, 2.2) increased the risk of higher IgD level when compared to other genotypes. Patients with higher IgD levels were more likely to suffer from arthritis (OR, 18). </p><p>Gershoni-Baruch et al. (2002) investigated 220 Jewish and Arab FMF patients from 178 unrelated families in whom both MEFV mutant alleles had been characterized. The M694V mutation (608107.0001) accounted for the majority of FMF chromosomes (62.9% among unrelated patients). Mutations V726A (608107.0003), M680I (608107.0004), E148Q (608107.0005), M694I (608107.0002), and the complex V726A-E148Q allele accounted for 13.8%, 7.6%, 5.3%, 5.3%, and 5.1% of FMF chromosomes, respectively. One hundred and five patients homozygous for the M694V mutation scored higher on disease severity, manifested more frequently articular and renal manifestations, and consumed higher doses of colchicine to control their attacks, compared to 39 patients compound heterozygous for M694V with either mutations V726A, M680I, or E148Q and compared to 15 homozygous for V726A or M680I. Compared to 12 V726A-E148Q homozygotes, M694V homozygotes did not differ on any of these effects other than the frequency of arthritis, which was higher among M694V homozygotes. Of the 42 patients with amyloidosis, 32 were M694V homozygotes, 4 were V726A-E148Q homozygotes, and the remaining 6 were compound heterozygotes for 1 of these alleles. The morbidity conferred by the complex V726A-E148Q allele by far outweighed that associated with the V726A allele, bearing evidence to the fact that the E148Q mutation is not a benign polymorphism. Gershoni-Baruch et al. (2002) concluded that the wide clinical variability of the disease seems to be partly affected by allelic heterogeneity and partly by additional genetic and/or environmental modifiers. </p><p>Gershoni-Baruch et al. (2003) concluded that severity of FMF and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene. They found that the male:female ratio (1.3) was higher among patients with amyloidosis (1.8) than among patients without amyloidosis (1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio, 4.27), the presence of the homozygous SAA-alpha/alpha genotype (104750) (OR, 2.99), the occurrence of arthritis attacks (OR, 2.43), and male sex (OR 1.73) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. </p><p>Booth et al. (1998) had found that the risk of developing secondary amyloidosis was higher in patients with rheumatoid arthritis or juvenile chronic arthritis when they carried the SAA1 alpha/alpha homozygous polymorphism of serum amyloid A1 (SAA1; 104750). </p><p>Cazeneuve et al. (2000) noted that the variable risk for patients with identical MEFV mutations to develop renal amyloidosis suggested the role of modifying genetic and/or environmental factors. Cazeneuve et al. (2000) investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. They found that the alpha/alpha homozygous SAA1 genotype was associated with a 7-fold increased risk for renal amyloidosis, compared with other SAA1 genotypes. This association, which was present whatever the MEFV genotype, was particularly marked in patients homozygous for M694V. The risk for male patients of developing renal amyloidosis was 4-fold higher than that for female patients. Polymorphisms in the SAA2 (104751) or the APOE (107741) gene did not appear to influence susceptibility to renal amyloidosis. Cazeneuve et al. (2000) found that the presence of only 1 SAA1-alpha allele did not confer an increased susceptibility to renal amyloidosis. </p><p>Nadeau (2001) discussed modifier genes in mice and humans, pointing out that these genes may modify the phenotype of mendelian traits by reducing penetrance, so-called dominance modification, and effects on expressivity and pleiotropy. The modification of FMF as to the occurrence of amyloidosis is an example of effects on pleiotropy. The SAA1 gene maps to 11p and the MEFV gene maps to 16p. </p><p>Grossman et al. (2019) reported a comprehensive characterization of the phenotypes of 57 patients with FMF who were homozygous for the M694V mutation (608107.0001) in the MEFV gene compared to the phenotypes of a cohort of 56 patients with FMF and other MEFV genotypes. Grossman et al. (2019) found that disease severity and average frequency of attacks per year, both before and after treatment, were higher in the M694V homozygote group compared to the cohort of patients with other MEFV genotypes, although there was no difference in the length of attacks or in the proportion of patients with abdominal, erysipelas-like erythema and fever-alone attacks. Grossman et al. (2019) also found that the colchicine dose was higher and the response to colchicine was lower in the M694V homozygote cohort. Additionally, the homozygote cohort had a higher overall rate of diseases associated with FMF, including Crohn disease, Behcet disease, ankylosing spondylitis and Henoch Schonlein purpura, but not fibromyalgia. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>The International FMF Consortium (1997) identified several disease-associated haplotypes, and found ancestral relationships among carrier chromosomes that had been separated for centuries. </p><p>Chen et al. (1998) found that of 34 disease alleles in FMF patients of Turkish origin, 19 carried the met694-to-val mutation (608107.0001) and 5 each carried the met680-to-ile (608107.0004) and the val726-to-ala (608107.0003) mutations. A mutation was not identified in 5 of the 34 alleles. </p><p>Each of the 4 mutations that were first identified as the basis for FMF segregates with 1 ancestral haplotype and all are clustered in exon 10 (608107.0001-608107.0004). In a search for additional MEFV mutations in 120 apparently nonfounder FMF chromosomes, Bernot et al. (1998) observed 8 novel mutations (see, e.g., 608107.0005) in exon 2 (E148Q, E167D, and T267I), exon 5 (F479L), and exon 10 (I692del, K695R, A744S, and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non-Ashkenazi Jews. Altogether, these new findings definitively established the marenostrin/pyrin-encoding gene as the MEFV locus responsible for FMF. </p><p>Aksentijevich et al. (1999) presented data on FMF mutations in non-Ashkenazi Jewish and Arab patients in whom they had not found mutations in earlier studies and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the 2 mutations that were novel, one (608107.0013) caused the same amino acid change as a previously known mutation, M680I (608107.0004), although the nucleotide change was different, and the other, P369S (608107.0014), was located in exon 3 (all 4 of the mutations initially described in MEFV were in exon 10). Consistent with the findings of others, the E148Q (608107.0005) mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicated an ancestral relationship between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicated reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helped account for recessive inheritance in an Ashkenazi family previously reported by Yuval et al. (1995) as an unusual case of dominantly inherited FMF. The presence of 3 frequent MEFV mutations in multiple Mediterranean populations strongly suggested a heterozygote advantage in this geographic region. </p><p>Cazeneuve et al. (1999) investigated 90 Armenian FMF patients from 77 unrelated families who were not selected through genetic linkage analysis. They found that 8 mutations, one of which (R408Q; 608107.0015) was new, accounted for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V (608107.0001) homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P = 0.0002 and P = 0.006, respectively). </p><p>Mansour et al. (2001) tested 79 Lebanese FMF patients for 15 mutations in the MEFV gene and found that they accounted for 67% of the total alleles. Mutations were detected in patients belonging to all Lebanese communities, including the Sunnite, Chiite, Druze, Maronite, Greek Orthodox, Greek Catholic, Syriac, and Armenian communities. The presence of FMF patients in this heterogeneous cohort of Lebanese patients supported the hypothesis of a selective advantage for FMF heterozygotes in the Mediterranean region. </p><p>Yilmaz et al. (2001) tested 450 Turkish FMF patients for 5 common MEFV gene mutations (M694V, M680I, E148Q, V726A, and M694I). The mutations accounted for 67.7% of the MEFV alleles, with the M694V mutation accounting for 51.6% of the alleles. Screening for these 5 mutations in a Turkish population sample of 100 showed 1 compound heterozygote and 20 heterozygotes, giving an allele frequency of 11%. Gershoni-Baruch et al. (2001) examined 146 unrelated FMF patients of Jewish and Arab descent for the same 5 founder mutations. The mutations accounted for 91% of FMF chromosomes. The overall carrier rates for the 4 most common FMF mutations (M680I, M694V, V726A, and E148Q) were 1:4.5 in 407 Ashkenazi Jews, 1:4.7 in 243 Moroccan Jews, 1:3.5 in 205 Iraqi Jews, and 1:4.3 in 318 Muslim Arabs. The overall frequency of low-penetrant mutations E148Q and V726A indicated that most individuals who have a genetic diagnosis of FMF remain asymptomatic. </p><p>Kogan et al. (2001) investigated the carrier rate of the most common MEFV mutations among different Jewish groups in Israel. Screening for the E148Q (608107.0005), V726A (608107.0003), and M694V (608107.0001) mutations was performed in 300 Ashkenazi, 101 Iraqi, and 120 Moroccan Jews, with a resulting overall carrier frequency in the 3 ethnic groups, respectively, of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and noncarriers of MEFV mutations was discerned. The frequency of subjects with 2 MEFV mutations who did not express FMF, the so-called phenotype III, was 1 in 300 in Ashkenazi Jews and 1 in 25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40- to 240-fold. These results affirmed the high carrier rate among the Jewish ethnic groups studied in Israel and suggested that most subjects with MEFV mutations are clinically unaffected. </p><p>El-Shanti et al. (2006) provided a detailed review of the range and distribution of MEFV mutations in the Arab population. </p><p>Fragouli et al. (2008) studied FMF in native Cretans, analyzing the 12 most frequent MEFV mutations in 71 patients and 158 healthy controls, and found that 59 (83.1%) of 71 FMF patients had at least 1 MEFV mutation, with 5 homozygotes and 54 heterozygotes; no mutations were detected in 16.9% of patients. Population genetic analysis showed an FMF carrier frequency in the healthy Cretan population of approximately 1:17 or about 6%. Fragouli et al. (2008) noted that this placed the Cretan population in the 'high risk' category in terms of FMF prevalence. </p><p>By mutational analysis of 376 Lebanese patients with FMF, Jalkh et al. (2008) found that the most common mutations were: M694V (28.98%), M694I (12.10%), V726A (19.28%), M680I (5.72%) and E148Q (10.10%). These mutations were estimated to be 7,000, 8,500, 15,000, 23,000, and 30,000 years old, respectively. Varying the mutation rate at 1 of the haplotype markers led to younger age estimates ranging from 3,625 to 18,650 years. A total of 333 different haplotypes were found, 31 of which had a frequency greater than 5% in the whole sample. A comparison of haplotype distributions among religious groups confirmed that Muslim subpopulations, including Shiites and Sunnites, as well as Christians, including Armenians who were formerly settled in the south-eastern part of Asia Minor (Cilicia), were all derived from an ancient common ancestral population, in which most of the MEFV mutations were already present with their respective associated haplotypes. </p><p>Bonyadi et al. (2009) tested for 5 common mutations in the MEFV gene (E148Q, M680I, M694V, M694I, and V726A) in 524 unrelated Iranian patients of Azeri Turkish origin with FMF and found their overall frequency to be 52%. Further analysis of 10 less common mutations enabled detection of approximately 9% of the unidentified alleles. The R761H mutation was the most frequently found of the rare alleles (4.7%), and the authors suggested that R761H should be included in routine molecular diagnosis of FMF patients from this ethnic group. Five different complex alleles were identified in 14 patients, including homozygosity for E167D (608107.0006)/F479L (608107.0008) in 2 patients. Bonyadi et al. (2009) noted that 43% of presumably mutated alleles remained elusive. </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</h4>
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<span class="mim-text-font">
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<p>The high allele frequencies for several different pyrin mutations in various populations suggest that the mutant alleles confer a selective advantage. Schaner et al. (2001) examined the ret finger protein (rfp) domain (which contains most of the disease-causing mutations) of pyrin during primate evolution. Amino acids that cause human disease are often present as wildtype in other species. This was found to be true at position 653, where a mutation was found for the first time by Schaner et al. (2001), 680, 681, 726, 744, and 761. For several of these human mutations, the mutant represents the reappearance of an ancestral amino acid state. Positive selection can be assessed using the ratio of nonsynonymous substitutions per nonsynonymous site, d(N), to synonymous substitutions per synonymous site, d(S). In theory, a d(N)/d(S) ratio equal to 1.0 indicates neutral change, a d(N)/d(S) ratio less than 1.0 indicates purifying selection, and a d(N)/d(S) ratio greater than 1.0 indicates positive selection. Examination of lineage-specific d(N)/d(S) ratios revealed a pattern consistent with the signature of episodic positive selection. Their data, together with previous human population studies, indicated that selective pressures may have caused functional evolution of pyrin in humans and other primates. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>22 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 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, MET694VAL
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SNP: rs61752717,
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gnomAD: rs61752717,
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ClinVar: RCV000002647, RCV000216751, RCV000763381, RCV001028046, RCV001197704, RCV001535935, RCV002262539, RCV002415387, RCV002464985, RCV003325449, RCV003335011, RCV005055344
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<p>In a large number of individuals affected with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) identified a 2080A-G transition in the pyrin gene, resulting in a met694-to-val (M694V) substitution. The affected individuals had 4 apparently distinct haplotypes. </p><p>The French FMF Consortium (1997) identified this A-G transition in the MEFV gene at nucleotide 1170 of their partial cDNA sequence. They referred to the mutation as the 'MED' variation because it was observed in affected members of families of various origins (Jewish, Armenian, Turkish, Arabian) sharing the MED haplotype. The ethnic diversity indicated that the mutation is ancient and confirms founder effect in the origin of a large fraction of FMF cases in the Mediterranean basin. </p><p>The MED mutation is found in about 80% of the FMF Jewish (Iraqi and North African) chromosomes. To see if the presence of this mutation could be correlated with particular traits of the disease, Dewalle et al. (1998) examined clinical features in a panel of 109 Jewish FMF patients with 0, 1, or 2 MED mutations. They showed that homozygosity for this mutation was significantly associated with a more severe form of the disease. In homozygous patients, the disease started earlier (mean age 6.4 vs 13.6) and both arthritis and pleuritis were twice as frequent as in patients with one or no M694V mutation. Moreover, all 3 of 3 patients with amyloidosis displayed 2 MED mutations. No association was found with fever, peritonitis, response to colchicine, and erysipeloid eruption. </p><p>Cazeneuve et al. (1999) found that the M694V allele had a frequency of 44.8% among 90 Armenian FMF patients from 77 unrelated families. They also found that the homozygous M694V genotype was associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes. </p><p>Yilmaz et al. (2001) found that the M694V allele had a frequency of 51.6% among 450 Turkish FMF patients. The carrier frequency in a Turkish population sample of 100 was 3%. </p><p>Bathelier et al. (2010) identified the M694V allele in 36 (6%) of 604 French patients with FMF: 7 patients were homozygous for the mutation and 29 were heterozygous. Heterozygosity for the M694V allele was found in 3 of 779 controls, which was significantly lower than among patients. Five of the 604 FMF patients had amyloidosis, and 2 of the patients with amyloidosis were homozygous for the M694V allele. Bathelier et al. (2010) concluded that M694V is a risk allele for the development of amyloidosis in FMF. Among patients carrying the mutant allele, 47% were of North African Jewish ancestry. In addition, the 3 controls who were heterozygous for the mutation were of Sephardic origin. </p><p>In a Lebanese female with autosomal recessive FMF, Masters et al. (2016) identified compound heterozygous missense mutations in the FMF gene: M694V and S242R (608107.0021). Each mutation was inherited from a parent: the unaffected mother carried the S242R variant in heterozygous state, suggesting incomplete penetrance of acute febrile neutrophilic dermatosis (AFND; 608068). The patient had periodic fevers, serositis, recurrent aphthous ulcers reminiscent of Behcet disease (BD; 109650), transient skin rashes/nodules, and joint pain that was partially controlled by colchicine. </p><p>Grossman et al. (2019) compared 57 patients with FMF who were homozygous for the M694V mutation to a cohort of 56 patients with FMF and other MEFV genotypes. They found that the M694V homozygotes had more severe disease, including more attacks per year, higher colchicine dosing, and lower colchicine response compared to the cohort of other genotypes. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 FAMILIAL MEDITERRANEAN FEVER</strong>
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</span>
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</h4>
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MEFV, MET694ILE
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<br />
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SNP: rs28940578,
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gnomAD: rs28940578,
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ClinVar: RCV000002648, RCV000002664, RCV000220431, RCV000589706, RCV000763380, RCV002262540, RCV004528066, RCV005016225
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<span class="mim-text-font">
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<p>In an Arabian family with familial Mediterranean fever (FMF; 249100), the French FMF Consortium (1997) found that affected members bearing an ARA2 haplotype had a 1172G-A transition in their partial MEFV cDNA sequence, resulting in a met694-to-ile (M694I) substitution. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, VAL726ALA
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<br />
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SNP: rs28940579,
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gnomAD: rs28940579,
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ClinVar: RCV000002649, RCV000220654, RCV000515437, RCV000623003, RCV000984975, RCV001535867, RCV002262541, RCV004739280
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</span>
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<span class="mim-text-font">
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<p>In a Druze family and in other familial Mediterranean fever (FMF; 249100) patients and carriers with the Druze (D) haplotype, the International FMF Consortium (1997) characterized a 2177T-C transition in the MEFV gene, resulting in a val726-to-ala (V726A) amino acid substitution in the protein. In FMF patients with the D haplotype and in patients with an ARM3 haplotype, the French FMF Consortium (1997) likewise found this T-C transition at nucleotide 1267 of their partial cDNA sequence. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, MET680ILE, 2040G-C
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<br />
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SNP: rs28940580,
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gnomAD: rs28940580,
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ClinVar: RCV000030179, RCV000222364, RCV001197705, RCV002251932, RCV002254152, RCV002262586, RCV002415433, RCV002477026, RCV004739312
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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 the affected offspring of a single Armenian family with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) found homozygosity for a 2040G-C transversion that resulted in a met680-to-ile (M680I) amino acid substitution in the pyrin protein. In Turkish and Armenian FMF patients with the ARM2 haplotype, the French FMF Consortium (1997) likewise found this G-C transversion at nucleotide 1130 of their partial cDNA sequence of the MEFV gene. Aksentijevich et al. (1999) found that the same amino acid change was produced by a 2040G-A transition; see 608107.0013. </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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MEFV, GLU148GLN
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<br />
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SNP: rs3743930,
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gnomAD: rs3743930,
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ClinVar: RCV000002651, RCV000002664, RCV000218652, RCV000513398, RCV000761446, RCV000768024, RCV002251861, RCV002262542, RCV002266255, RCV002326658, RCV003224086, RCV004528067, RCV005208118
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (FMF; 249100), has been reclassified based on the findings of Medlej-Hashim et al. (2002). </p><p>Bernot et al. (1998) observed a G-to-C transversion in exon 2 of the MEFV gene, resulting in a glu148-to-gln (E148Q) substitution, as a novel mutation among 120 apparently nonfounder FMF chromosomes. The mutation was found on 29 of 120 (24%) of patient chromosomes and on 3 of 131 control chromosomes. </p><p>Aksentijevich et al. (1999) found that a high gene frequency of this glu148-to-gln (E148Q) recessive mutation and reduced penetrance accounted for the anomalous pattern of inheritance in an Ashkenazi family previously reported by Yuval et al. (1995) as an unusual case of dominantly inherited FMF. </p><p>Yilmaz et al. (2001) found that the E148Q allele had a frequency of 3.2% among 450 Turkish FMF patients. The carrier frequency in a Turkish population sample of 100 was 12%. </p><p>Medlej-Hashim et al. (2002) pointed out that E148Q may be a polymorphism. Its role in connection with mutations on the other allele, the MEFV locus, and on a second mutation on the same allele is unclear. Furthermore, the E148V mutation (608107.0017), found in 1 Lebanese patient by Medlej-Hashim et al. (2002), gives the same digestion pattern on Southern blot as does E148Q when AvaI restriction enzyme is used in the RFLP detection method. </p><p>Otsuka et al. (2019) reported a 32-year-old Japanese man with adult-onset fever, tonsillitis, and skin rash associated with leukocytosis, increased C-reactive protein, increased ferritin, and activation of monocytes. His rash consisted of painless papules and plaques. Skin biopsy showed neutrophilic dermatosis, and he was diagnosed clinically with adult-onset Sweet disease (see 608068). He showed a favorable response to colchicine and low-dose corticosteroids. Genetic analysis identified a heterozygous E148Q variant in the MEFV gene, which the authors noted is found in about 20% of healthy individuals in Japan. Functional studies of the variant were not performed, but Otsuka et al. (2019) suggested that the variant may have contributed to the development of the disorder. </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>.0006 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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MEFV, GLU167ASP
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<br />
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SNP: rs104895079,
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gnomAD: rs104895079,
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ClinVar: RCV000002652, RCV000587727, RCV000588525, RCV001262294, RCV002262543, RCV003230342, RCV005016226
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|
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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>Bernot et al. (1998) observed a G-to-C transversion in exon 2 of the MEFV gene, resulting in a glu167-to-asp (E167D) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; 249100) chromosomes. The mutation was found in a single Armenian family and in none of 205 control chromosomes. </p><p>In 2 unrelated Iranian patients of Azeri Turkish origin with FMF Bonyadi et al. (2009) identified homozygosity for a complex allele involving E167D and F479L (608107.0008). </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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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MEFV, THR267ILE
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<br />
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|
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SNP: rs104895081,
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gnomAD: rs104895081,
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|
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ClinVar: RCV000002653, RCV000991330, RCV000996177, RCV001535446, RCV002262544, RCV004532273, RCV005016227
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|
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|
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</span>
|
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</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bernot et al. (1998) observed a C-to-T transition in exon 2 of the MEFV gene, resulting in a thr267-to-ile (T267I) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; 249100) chromosomes. The mutation was found in a single family of non-Ashkenazi Jewish origin and in none of 205 control chromosomes. </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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|
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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>.0008 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, PHE479LEU
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<br />
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|
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SNP: rs104895083,
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gnomAD: rs104895083,
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ClinVar: RCV000002654, RCV000508324, RCV000587727, RCV002262545, RCV003230343, RCV003466786, RCV004771453, RCV005016228
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bernot et al. (1998) observed a C-to-G transversion in exon 5 of the MEFV gene, resulting in a phe479-to-leu (F479L) substitution, as a novel mutation among 120 apparently nonfounder familial Mediterranean fever (FMF; 249100) chromosomes. The mutation was found in a single Armenian family and in none of 205 control chromosomes. </p><p>See 608107.0006 and Bonyadi et al. (2009). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, 3-BP DEL, ILE692DEL
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs104895093, rs121907890,
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|
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gnomAD: rs104895093,
|
|
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|
|
ClinVar: RCV000083737, RCV000487146, RCV002262640, RCV003460764
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Arab family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed deletion of AAT from 2 adjacent codons (ile692 and met693) in exon 10 of the MEFV gene, resulting in transformation into a single ATG codon after the deletion (ile692del) and conservation of the reading frame. The mutation was not found in any of 198 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, LYS695ARG
|
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|
|
|
<br />
|
|
|
|
SNP: rs104895094,
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|
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|
|
|
gnomAD: rs104895094,
|
|
|
|
|
|
ClinVar: RCV000002656, RCV000196026, RCV000213470, RCV000415431, RCV000508192, RCV000622573, RCV000768021, RCV001270033, RCV002262546, RCV003224087, RCV003389035, RCV004739281
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 non-Ashkenazi Jewish families and 1 Armenian family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed an A-to-G transition in exon 10 of the MEFV gene, resulting in a lys695-to-arg (K695R) substitution. The mutation was also found in 1 of 198 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, ALA744SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61732874,
|
|
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|
|
|
gnomAD: rs61732874,
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|
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|
|
ClinVar: RCV000002657, RCV000213702, RCV000768020, RCV000999738, RCV001535864, RCV001770031, RCV002262547, RCV002415388, RCV004532274
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Armenian family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed a G-to-T transversion in exon 10 of the MEFV gene, resulting in an ala744-to-ser (A744S) substitution. The mutation was not found in 198 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, ARG761HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104895097,
|
|
|
|
|
|
gnomAD: rs104895097,
|
|
|
|
|
|
ClinVar: RCV000002658, RCV000217233, RCV000763379, RCV001536101, RCV002262548, RCV002512683, RCV003466787, RCV004739282
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Armenian family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed a G-to-A transition in exon 10 of the MEFV gene, resulting in an arg761-to-his (R761H) substitution. The mutation was not found in 198 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 FAMILIAL MEDITERRANEAN FEVER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, MET680ILE, 2040G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940580,
|
|
|
|
|
|
gnomAD: rs28940580,
|
|
|
|
|
|
ClinVar: RCV000002659, RCV000216518, RCV001283820, RCV002262549, RCV004724727, RCV005016229
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Aksentijevich et al. (1999) described a 2040G-A transition in the MEFV gene in familial Mediterranean fever (FMF; 249100) causing an M680I amino acid substitution. A G-C transversion of the same nucleotide (608107.0004) resulted in the same amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, PRO369SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs11466023,
|
|
|
|
|
|
gnomAD: rs11466023,
|
|
|
|
|
|
ClinVar: RCV000002660, RCV000215679, RCV000416092, RCV001251298, RCV002262550, RCV002433442
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (249100), has been reclassified based on the findings of Berg et al. (2013). </p><p>In patients with FMF (249100), Aksentijevich et al. (1999) found a pro369to-ser (P369S) mutation in exon 3 of the MEFV gene. They noted that 4 of the mutations initially described in MEFV were in exon 10. The mutation was found on the same allele with the E148Q mutation (see 608107.0005) in 2 patients and without E148Q in 3 other patients, and in 1 of 222 control chromosomes. </p><p>Berg et al. (2013) reclassified the P369S mutation as 'considered to imply carrier status' for a recessive disorder. They noted that the P369S and R408Q (608107.0015) mutations had been reported in cis as a single allele resulting in a highly variable clinical phenotype. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, ARG408GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs11466024,
|
|
|
|
|
|
gnomAD: rs11466024,
|
|
|
|
|
|
ClinVar: RCV000002661, RCV000218029, RCV000224408, RCV001251298, RCV002262551, RCV002362552
|
|
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|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled FAMILIAL MEDITERRANEAN FEVER (249100), has been reclassified based on the findings of Berg et al. (2013). </p><p>In a genotypic study of 90 Armenian FMF (249100) patients from 77 unrelated families, Cazeneuve et al. (1999) identified a novel mutation, arg408-to-gln (R408Q) in the MEFV gene. The mutation was identified in 1 patient in cis with the E148Q (608107.0005) and P369S (608107.0014) mutations. </p><p>Berg et al. (2013) reclassified the R408Q mutation as 'considered to imply carrier status' for a recessive disorder. They noted that the R408Q and P369S (608107.0014) mutations had been reported in cis as a single allele resulting in a highly variable clinical phenotype. </p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, ARG653HIS
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<br />
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SNP: rs104895085,
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gnomAD: rs104895085,
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ClinVar: RCV000002662, RCV000255083, RCV003466788, RCV005016230
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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 the study of the evolution of pyrin in primates, Schaner et al. (2001) reported a 1958G-A transition in the MEFV gene that resulted in an arg653-to-his (R653H) change. They pointed out that the human wildtype amino acid, arginine, is seen only in gorilla, chimp, and human. All other species (except dwarf lemur) contain histidine at this position. Thus, histidine is most likely the ancestral amino acid, and the human disease mutation from arginine to histidine replicates this ancestral (and highly conserved) state. A similar kind of pattern was seen in the evolutionary history of other codons. </p>
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</span>
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</div>
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<div>
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</div>
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</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>.0017 FAMILIAL MEDITERRANEAN FEVER</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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MEFV, GLU148VAL
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<br />
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SNP: rs104895076,
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gnomAD: rs104895076,
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ClinVar: RCV000002663, RCV000216721, RCV000415966, RCV002262552, RCV002482818, RCV003125825, RCV003125826
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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>Medlej-Hashim et al. (2002) described the glu148-to-val mutation (E148V) in 1 Lebanese patient with familial Mediterranean fever (FMF; 249100). They pointed out that the usual RFLP detection method used for E148Q (608107.0005), which may represent a polymorphism or at the most a weakly pathogenic allele, gives the same restriction pattern as does E148V. When AvaI restriction enzyme is used the 2 mutations cause the same pattern; different patterns are created by E148Q and E148V when MvaI enzyme is used. </p>
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</span>
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<div>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0018 FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT</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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MEFV, GLU148GLN AND MET694ILE
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<br />
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ClinVar: RCV000002648, RCV000002651, RCV000002664, RCV000218652, RCV000220431, RCV000513398, RCV000589706, RCV000761446, RCV000763380, RCV000768024, RCV002251861, RCV002262540, RCV002262542, RCV002266255, RCV002326658, RCV003224086, RCV004528066, RCV004528067, RCV005016225, RCV005208118
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated families with autosomal dominant FMF (134610), Booth et al. (2000) identified 2 mutations in the MEFV gene on the same allele: a glu148-to-gln (E148Q) substitution and a met694-to-ile (M694I; 608107.0002) substitution. One family was Turkish and the other Indian. Complete sequencing of the MEFV gene failed to identify mutations on the second allele. Several asymptomatic individuals from both families carried the mutation, indicating disease penetrance of 50 to 90%. The clinical features of FMF in these families were classical in every respect, including favorable response to colchicine; however, no patients developed amyloidosis. </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>.0019 FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT</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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MEFV, 3-BP DEL, 2080ATG
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<br />
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SNP: rs104895091,
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gnomAD: rs104895091,
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ClinVar: RCV000002665, RCV000083740, RCV000757455
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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 3 unrelated British families with autosomal dominant FMF (134610), Booth et al. (2000) identified heterozygosity for a 3-bp deletion in the MEFV gene, resulting in deletion of residue met694. This codon is the site of 2 other common mutations in the MEFV gene (M694V; 608107.0001 and M694I; 608107.0002). The clinical features of FMF in these families were classical in every respect, including favorable response to colchicine. Incomplete penetrance was observed. Only 1 patient had amyloidosis. </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>.0020 FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT</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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MEFV, HIS478TYR
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<br />
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SNP: rs104895105,
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ClinVar: RCV000002666, RCV000083696, RCV001562614, RCV003125827
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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 affected members of a Spanish kindred with autosomal dominant FMF (134610), Aldea et al. (2004) identified a heterozygous 1432C-T transition in exon 5 of the MEFV gene, resulting in a his478-to-tyr (H478Y) substitution in the coiled-coil domain of the protein. No additional mutations were detected in the MEFV gene or in the TNFRSF1A gene (191190). Affected individuals showed a severe form of the disorder, with renal amyloidosis developing in the older patients. Although there was no response to colchicine, patients did show favorable response to monoclonal antibodies against TNF-alpha (TNFA; 191160). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0021 NEUTROPHILIC DERMATOSIS, ACUTE FEBRILE</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">
|
|
FAMILIAL MEDITERRANEAN FEVER, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
MEFV, SER242ARG ({dbSNP rs104895127})
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<br />
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SNP: rs104895127,
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|
|
gnomAD: rs104895127,
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|
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|
|
ClinVar: RCV000083793, RCV001172095, RCV001174523, RCV005016371
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Acute Febrile Neutrophilic Dermatosis</em></strong></p><p>
|
|
In 12 affected members of a large 3-generation Belgian family with acute febrile neutrophilic dermatosis (AFND; 608068), Masters et al. (2016) identified a heterozygous c.726C-G transversion in exon 2 of the MEFV gene, resulting in a ser242-to-arg (S242R) substitution at a conserved residue in mammals. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was seen in 1 of 122,836 chromosomes in the ExAC database, in a Colombian male for whom clinical information was not available (1000 Genomes Project database). The same heterozygous S242R mutation was subsequently identified in 2 additional pedigrees (A and C) with an overlapping phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation enhanced the formation of apoptosis-associated speck-like proteins compared to controls. Downstream of ASC, the S242R mutation resulted in activation of CASP1 (147678), as well as increased secretion of IL1B compared to wildtype. Further studies showed that the mutation impaired phosphorylation of S242, which resulted in removal of inhibitory 14-3-3 proteins (see, e.g., 609009 and 605066) and constitutive activation of pyrin. One patient was successfully treated with anakinra, which blocks IL1B. Masters et al. (2016) noted that the molecular mechanism resulting from the S242R mutation differed from that of FMF-associated mutations M694V, M680I, and V726A, which had no appreciable effect on 14-3-3 binding. Of note, the carrier mother in family C did not have neutrophilic dermatosis, but she did have some features of the disorder, including recurrent fevers and elevated acute-phase reactants. These findings suggested incomplete penetrance or clinical variability. </p><p><strong><em>Familial Mediterranean Fever, Autosomal Recessive</em></strong></p><p>
|
|
In a Lebanese female (family B) with autosomal recessive familial Mediterranean fever (FMF; 249100), Masters et al. (2016) identified compound heterozygous missense mutations in the FMF gene: M694V (608107.0001) and S242R. Each mutation was inherited from a parent: the unaffected mother carried the S242R variant in heterozygous state, suggesting incomplete penetrance of AFND. The patient had periodic fevers, serositis, recurrent aphthous ulcers reminiscent of Behcet disease (BD; 109650), transient skin rashes/nodules, and joint pain that was partially controlled by colchicine. </p><p>Kiyota et al. (2020) reported a 45-year-old Japanese man with a systemic autoinflammatory disorder with intermittent fever and amyloidosis, consistent with FMF, as well as pustular dermatosis with neutrophilic aggregates since childhood. The authors noted that he had abdominal symptoms, rather than classic serositis, and that the skin problems had been the main symptom since chilhood, suggesting a phenotype that overlapped with AFND (608068). Genetic analysis identified compound heterozygous missense variants in the MEFV gene (S242R and E148Q, 608107.0005). His unaffected mother was heterozygous for the S242R mutation, indicating incomplete penetrance of AFND. Functional studies of the variants were not performed, but the authors suggested that the E148Q polymorphism may act as a disease modifier. </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>.0022 NEUTROPHILIC DERMATOSIS, ACUTE FEBRILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MEFV, GLU244LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1959081392,
|
|
|
|
|
|
|
|
ClinVar: RCV001174525
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a Spanish family with acute febrile neutrophilic dermatosis (AFND; 608068), Moghaddas et al. (2017) identified a heterozygous c.730G-A transition in exon 2 of the MEFV gene, resulting in a glu244-to-lys (E244K) substitution at a highly conserved residue. The mutation, which was found by direct sequencing of exon 2 of the MEFV gene, was not found in the 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in 250 healthy Spanish controls. Patient-derived monocytes transfected with the mutation showed augmented ASC (606838) speck formation both at baseline and upon LPS exposure, increased CASP1 activity, increased IL1B and IL18, and increased inflammatory cell death compared to controls. These findings were associated with reduced phosphorylation of the MEFV 14-3-3 binding motif and reduced 14-3-3 binding compared to controls, ultimately resulting in inappropriate activation of MEFV. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
|
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Aksentijevich, I., Torosyan, Y., Samuels, J., Centola, M., Pras, E., Chae, J. J., Oddoux, C., Wood, G., Azzaro, M. P., Palumbo, G., Giustolisi, R., Pras, M., Ostrer, H., Kastner, D. L.
|
|
<strong>Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.</strong>
|
|
Am. J. Hum. Genet. 64: 949-962, 1999.
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[PubMed: 10090880]
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[Full Text: https://doi.org/10.1086/302327]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Aldea, A., Campistol, J. M., Arostegui, J. I., Rius, J., Maso, M., Vives, J., Yague, J.
|
|
<strong>A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?</strong>
|
|
Am. J. Med. Genet. 124A: 67-73, 2004.
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[PubMed: 14679589]
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[Full Text: https://doi.org/10.1002/ajmg.a.20296]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bathelier, C., Lenoir, G., Lucotte, G.
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<strong>Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients. (Letter)</strong>
|
|
Genet. Counsel. 21: 461-466, 2010.
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[PubMed: 21290976]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee, K., Schmitt, C. P., Wilhelmsen, K. C., Evans, J. P.
|
|
<strong>An informatics approach to analyzing the incidentalome.</strong>
|
|
Genet. Med. 15: 36-44, 2013.
|
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[PubMed: 22995991]
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[Full Text: https://doi.org/10.1038/gim.2012.112]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bernot, A., da Silva, C., Petit, J.-L., Cruaud, C., Caloustian, C., Castet, V., Ahmed-Arab, M., Dross, C., Dupont, M., Cattan, D., Smaoui, N., Dode, C., and 10 others.
|
|
<strong>Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).</strong>
|
|
Hum. Molec. Genet. 7: 1317-1325, 1998.
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[PubMed: 9668175]
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[Full Text: https://doi.org/10.1093/hmg/7.8.1317]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bonyadi, M., Esmaeili, M., Jalali, H., Somi, M. H., Ghaffari, A., Rafeey, M., Sakha, K., Lotfalizadeh, N., Pourhassan, A., Khoshbaten, M., Ardalan, M. R., Laghaeian, N.
|
|
<strong>MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.</strong>
|
|
Clin. Genet. 76: 477-480, 2009.
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|
[PubMed: 19863562]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01270.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">
|
|
Booth, D. R., Booth, S. E., Gillmore, J. D., Hawkins, P. N., Pepys, M. B.
|
|
<strong>SAA1 alleles as risk factors in reactive systemic AA amyloidosis.</strong>
|
|
Amyloid 5: 262-265, 1998.
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|
|
[PubMed: 10036584]
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[Full Text: https://doi.org/10.3109/13506129809007299]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Booth, D. R., Gillmore, J. D., Lachmann, H. J., Booth, S. E., Bybee, A., Soyturk, M., Akar, S., Pepys, M. B., Tunca, M., Hawkins, P. N.
|
|
<strong>The genetic basis of autosomal dominant familial Mediterranean fever.</strong>
|
|
Quart. J. Med. 93: 217-221, 2000.
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[PubMed: 10787449]
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[Full Text: https://doi.org/10.1093/qjmed/93.4.217]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Genevieve, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.-C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S.
|
|
<strong>Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.</strong>
|
|
Am. J. Hum. Genet. 67: 1136-1143, 2000.
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[PubMed: 11017802]
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Shoham, N. G., Centola, M., Mansfield, E., Hull, K. M., Wood, G., Wise, C. A., Kastner, D. L.
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<strong>The spectrum of familial Mediterranean fever (FMF) mutations.</strong>
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Ada Hamosh - updated : 03/03/2021<br>Hilary J. Vernon - updated : 08/10/2020<br>Cassandra L. Kniffin - updated : 06/09/2020<br>Bao Lige - updated : 03/13/2019<br>Ada Hamosh - updated : 10/22/2014<br>Ada Hamosh - updated : 5/31/2013<br>Cassandra L. Kniffin - updated : 3/5/2013<br>George E. Tiller - updated : 11/1/2010<br>Marla J. F. O'Neill - updated : 1/13/2010<br>Cassandra L. Kniffin - updated : 10/15/2008<br>Marla J. F. O'Neill - updated : 7/10/2008<br>Patricia A. Hartz - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/22/2007<br>Paul J. Converse - updated : 8/16/2006<br>Cassandra L. Kniffin - updated : 3/15/2006<br>Cassandra L. Kniffin - updated : 6/23/2004
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