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<title>
Entry
- *601253 - CAVEOLIN 3; CAV3
- OMIM
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<span class="h4">*601253</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#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">
<a href="#description">Description</a>
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Genome
</a>
</span>
</span>
</div>
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000182533;t=ENST00000343849" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=859" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=601253" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
<span class="panel-title">
<span class="small">
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> DNA
</a>
</span>
</span>
</div>
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000182533;t=ENST00000343849" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001234,NM_033337" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_033337" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=601253" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
<span class="panel-title">
<span class="small">
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Protein
</a>
</span>
</span>
</div>
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://hprd.org/summary?hprd_id=03154&isoform_id=03154_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>
<div><a href="https://www.proteinatlas.org/search/CAV3" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/protein/3059125,3089435,3150445,3150449,3182930,4502589,9930105,15451860,46854792,74353789,74354491,74354493,119584349,119584350,158257216,1095447993" 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>
<div><a href="https://www.uniprot.org/uniprotkb/P56539" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
<span class="panel-title">
<span class="small">
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Gene Info</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="http://biogps.org/#goto=genereport&id=859" 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>
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000182533;t=ENST00000343849" 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>
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CAV3" 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>
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CAV3" 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>
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+859" 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>
<dd><a href="http://v1.marrvel.org/search/gene/CAV3" 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>
<dd><a href="https://monarchinitiative.org/NCBIGene:859" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/859" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000343849.3&hgg_start=8733802&hgg_end=8746758&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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
<span class="panel-title">
<span class="small">
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1529" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601253[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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
<span class="panel-title">
<span class="small">
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9660;</span> Variation
</a>
</span>
</span>
</div>
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601253[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>
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000182533" 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>
<div><a href="https://www.ebi.ac.uk/gwas/search?query=CAV3" 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&nbsp;</a></div>
<div><a href="https://www.gwascentral.org/search?q=CAV3" 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&nbsp;</a></div>
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CAV3" 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>
<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Locus Specific DBs</div>
<div id="mimLocusSpecificDBsFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=CAV3" title="Zhejiang University-Adinovo Center CAV3 Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/CAV3" title="Limb-Girdle Muscular Dystrophy type 1C" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Limb-Girdle Muscular Dystr…</a></div>
</div>
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CAV3&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>
<div><a href="https://www.pharmgkb.org/gene/PA26109" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/gene/HGNC:1529" 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>
<div><a href="https://www.mousephenotype.org/data/genes/MGI:107570" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
<div><a href="http://v1.marrvel.org/search/gene/CAV3#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>
<div><a href="http://www.informatics.jax.org/marker/MGI:107570" 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>
<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>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/859/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>
<div><a href="https://www.orthodb.org/?ncbi=859" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000301;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
<div><a href="https://zfin.org/ZDB-GENE-050522-426" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
<span class="panel-title">
<span class="small">
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cellular Pathways</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:859" 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>
<div><a href="https://reactome.org/content/query?q=CAV3&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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 711265009, 83978005<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Gene description">
<span class="text-danger"><strong>*</strong></span>
601253
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
CAVEOLIN 3; CAV3
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
M-CAVEOLIN
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="approvedGeneSymbols" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CAV3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CAV3</a></em></strong>
</span>
</p>
</div>
<div>
<a id="cytogeneticLocation" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: <a href="/geneMap/3/27?start=-3&limit=10&highlight=27">3p25.3</a>
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:8733802-8746758&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'})">3:8,733,802-8,746,758</a> </span>
</em>
</strong>
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<a id="geneMap" class="mim-anchor"></a>
<div style="margin-bottom: 10px;">
<span class="h4 mim-font">
<strong>Gene-Phenotype Relationships</strong>
</span>
</div>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
<span class="hidden-sm hidden-xs pull-right">
<a href="/clinicalSynopsis/table?mimNumber=192600,123320,611818,614321,606072" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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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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<span class="mim-font">
<a href="/geneMap/3/27?start=-3&limit=10&highlight=27">
3p25.3
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</td>
<td>
<span class="mim-font">
Cardiomyopathy, familial hypertrophic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/192600"> 192600 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</td>
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<td>
<span class="mim-font">
Creatine phosphokinase, elevated serum
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123320"> 123320 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
Long QT syndrome 9
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</td>
<td>
<span class="mim-font">
<a href="/entry/611818"> 611818 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
</span>
</td>
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<tr>
<td>
<span class="mim-font">
Myopathy, distal, Tateyama type
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614321"> 614321 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
</span>
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<td>
<span class="mim-font">
Rippling muscle disease 2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606072"> 606072 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Caveolin-3 (M-caveolin) is the muscle-specific form of the caveolin protein family, which also includes caveolin-1 (CAV1; <a href="/entry/601047">601047</a>) and caveolin-2 (CAV2; <a href="/entry/601048">601048</a>). Caveolins are the principal protein components of caveolae ('little caves'), 50 to 100 nm invaginations found in most cell types which represent appendages or subcompartments of plasma membranes (<a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9537420" 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>Caveolin-3 plays a role in muscle development and physiology. In adult muscle, it is present throughout the T tubule system, but is clustered in subsarcolemmal areas critical for the electrical transmission of the contractile impulse. In the sarcolemma, caveolin-3 belongs to the dystrophin-glycoprotein complex and confers stability to the muscle cell membrane. In addition to these structural roles, caveolin-3 has functional roles in signaling pathways and energy metabolism (review by <a href="#14" class="mim-tip-reference" title="Gazzerro, E., Sotgia, F., Bruno, C., Lisanti, M. P., Minetti, C. &lt;strong&gt;Caveolinopathies: from the biology of caveolin-3 to human diseases.&lt;/strong&gt; Europ. J. Hum. Genet. 18: 137-145, 2010. Note: Erratum: Europ. J. Hum. Genet. 17: 1692 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19584897/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19584897&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19584897[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2009.103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19584897">Gazzerro et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19584897" 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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<br />
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</div>
<div>
<a id="cloning" class="mim-anchor"></a>
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
<p>To identify other putative members of the G protein-associated caveolin gene family, <a href="#37" class="mim-tip-reference" title="Tang, Z., Scherer, P. E., Okamoto, T., Song, K., Chu, C., Kohtz, D. S., Nishimoto, I., Lodish, H. F., Lisanti, M. P. &lt;strong&gt;Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.&lt;/strong&gt; J. Biol. Chem. 271: 2255-2261, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8567687/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8567687&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.271.4.2255&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8567687">Tang et al. (1996)</a> searched existing databases for genomic sequences related to the protein sequence of caveolin-1. They identified a rat sequence that appeared to encode a novel caveolin-like gene and designed oligonucleotide primers with which to amplify purified rat genomic DNA. They designated the new gene caveolin-3 (CAV3). Rat caveolin-3 is approximately 65% identical and 85% similar to rat caveolin-1. The authors noted that a single stretch of amino acids (FEDVIAEP) is identical in caveolin-1, -2, and -3, and may represent a 'caveolin signature sequence' characteristic of this family. <a href="#37" class="mim-tip-reference" title="Tang, Z., Scherer, P. E., Okamoto, T., Song, K., Chu, C., Kohtz, D. S., Nishimoto, I., Lodish, H. F., Lisanti, M. P. &lt;strong&gt;Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.&lt;/strong&gt; J. Biol. Chem. 271: 2255-2261, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8567687/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8567687&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.271.4.2255&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8567687">Tang et al. (1996)</a> further characterized the biochemistry, cellular localization, and tissue specificity of caveolin-3. They detected the CAV3 transcript only in rat skeletal muscle, diaphragm, and heart tissues, but noted that CAV3 expression was specific to the endothelial cells surrounding the muscle fibers. Additionally, they observed that a caveolin-3-derived polypeptide conserved in caveolin-1 either suppresses or stimulates the basal GTPase activity of purified heterotrimeric G proteins (see <a href="/entry/600239">600239</a>) in a concentration-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8567687" 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="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> cloned the CAV3 gene and found that the cDNA encodes an open reading frame of 150 amino acids with 96% homology to the rat and mouse sequences. CAV3 mRNA was expressed exclusively in cardiac and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> stated that caveolin-3 contains a 20-amino acid scaffolding domain (residues 54 to 73) that is critical for homo-oligomerization and for interaction with several caveolin-associated signaling molecules. A 33-amino acid hydrophobic domain (residues 74 to 106) of caveolin-3, which spans the membrane, is thought to form a hairpin loop within the cell membrane, allowing both the amino- and carboxy-terminal domains to face the cytoplasm. Comparison of caveolins-1, -2, and -3 with caveolins-1 and -2 of Caenorhabditis elegans showed that only 12 amino acid residues are invariant between worms and man. <a href="#29" class="mim-tip-reference" title="Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G. &lt;strong&gt;Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning.&lt;/strong&gt; Hum. Molec. Genet. 14: 1727-1743, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15888488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15888488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi179&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15888488">Nixon et al. (2005)</a> noted that CAV3 shares 72% identity with its zebrafish homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15888488+9537420" 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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<br />
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<div>
<a id="geneStructure" class="mim-anchor"></a>
<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Gene Structure</strong>
</span>
</h4>
</div>
<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#25" class="mim-tip-reference" title="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> determined that the CAV3 gene contains 2 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536092" 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="mapping" class="mim-anchor"></a>
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<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p>By fluorescence in situ hybridization, <a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> and <a href="#25" class="mim-tip-reference" title="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> mapped the CAV3 gene to chromosome 3p25. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9536092+9537420" 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 map the CAV3 gene more precisely, <a href="#34" class="mim-tip-reference" title="Sotgia, F., Minetti, C., Lisanti, M. P. &lt;strong&gt;Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.&lt;/strong&gt; FEBS Lett. 452: 177-180, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10386585/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10386585&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0014-5793(99)00658-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10386585">Sotgia et al. (1999)</a> isolated 3 independent BAC clones containing the human CAV3 gene. Using a PCR-based approach, they determined that these clones contained both exons 1 and 2 of the CAV3 gene. In addition, they performed microsatellite marker analysis of these BAC clones, using a panel of 13 markers that are known to map within the 3p25 region. They identified 3 markers within these BAC clones, one of which, D3S18, is a marker for 2 known human diseases, von Hippel-Lindau disease (VHL; <a href="/entry/193300">193300</a>) and 3p- syndrome. Two of the markers were known to map in the vicinity of the 3-prime end of the oxytocin receptor gene (OXTR; <a href="/entry/167055">167055</a>). <a href="#34" class="mim-tip-reference" title="Sotgia, F., Minetti, C., Lisanti, M. P. &lt;strong&gt;Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.&lt;/strong&gt; FEBS Lett. 452: 177-180, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10386585/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10386585&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0014-5793(99)00658-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10386585">Sotgia et al. (1999)</a> showed that these BACs contained all 4 exons of the oxytocin receptor gene, and that the genes encoding CAV3 and OXTR are located approximately 7 to 10 kb apart and are transcribed in opposite orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10386585" 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="geneFunction" class="mim-anchor"></a>
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<strong>Gene Function</strong>
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<p><a href="#25" class="mim-tip-reference" title="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> showed that caveolin-3 copurifies with dystrophin (<a href="/entry/300377">300377</a>) in rat skeletal muscle membrane, suggesting a role in muscular dystrophy. The authors noted, however, that a significant fraction of the caveolin present in the rat skeletal muscle did not copurify with dystrophin, suggesting that caveolin is not associated exclusively with the dystrophin-glycoprotein complex (DGC) in muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536092" 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>Dysferlin (DYSF; <a href="/entry/603009">603009</a>) is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited forms of muscular dystrophy designated Miyoshi myopathy (MM; <a href="/entry/254130">254130</a>) and limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), respectively. <a href="#24" class="mim-tip-reference" title="Matsuda, C., Hayashi, Y. K., Ogawa, M., Aoki, M., Murayama, K., Nishino, I., Nonaka, I., Arahata, K., Brown, R. H., Jr. &lt;strong&gt;The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.&lt;/strong&gt; Hum. Molec. Genet. 10: 1761-1766, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11532985/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11532985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.17.1761&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11532985">Matsuda et al. (2001)</a> reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae. Abnormal localization of dysferlin was seen in muscles from patients diagnosed with limb-girdle muscular dystrophy type 1C (LGMD1C), reclassified as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>) by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a>, including one with a novel missense mutation in CAV3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30055862+11532985" 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 3p- syndrome results from a hemizygous deletion of 3pter-p25 and is characterized by growth retardation, specific craniofacial features (microcephaly, ptosis, micrognathia), mental retardation, and cardiac septal defects (<a href="#7" class="mim-tip-reference" title="Drumheller, T., McGillivray, B. C., Behrner, D., MacLeod, P., McFadden, D. E., Roberson, J., Venditti, C., Chorney, K., Chorney, M., Smith, D. I. &lt;strong&gt;Precise localisation of 3p25 breakpoints in four patients with the 3p- syndrome.&lt;/strong&gt; J. Med. Genet. 33: 842-847, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8933338/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8933338&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.10.842&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8933338">Drumheller et al., 1996</a>). <a href="#34" class="mim-tip-reference" title="Sotgia, F., Minetti, C., Lisanti, M. P. &lt;strong&gt;Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.&lt;/strong&gt; FEBS Lett. 452: 177-180, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10386585/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10386585&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0014-5793(99)00658-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10386585">Sotgia et al. (1999)</a> suggested that the CAV3 gene may be deleted in 3p- syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8933338+10386585" 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="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Skeletal Muscle Phenotypes</em></strong></p><p>
Mutations in the CAV3 gene can cause different skeletal muscle phenotypes, including rippling muscle disease-2 (RMD2; <a href="/entry/606072">606072</a>); isolated hyperCKemia (<a href="/entry/123320">123320</a>); and distal myopathy (MPDT; <a href="/entry/614321">614321</a>). A form of limb-girdle muscular dystrophy (LGMD1C) caused by mutation in the CAV3 gene was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as RMD2. Many patients show an overlap of these skeletal muscle entities, and some authors have suggested that the caveolinopathies constitute a clinical continuum. Moreover, there are no genotype/phenotype correlations, the same mutation can cause heterogeneous phenotypes, and there is intrafamilial variability. Most of the mutations cause a loss of caveolin-3 in skeletal muscle biopsy (review by <a href="#14" class="mim-tip-reference" title="Gazzerro, E., Sotgia, F., Bruno, C., Lisanti, M. P., Minetti, C. &lt;strong&gt;Caveolinopathies: from the biology of caveolin-3 to human diseases.&lt;/strong&gt; Europ. J. Hum. Genet. 18: 137-145, 2010. Note: Erratum: Europ. J. Hum. Genet. 17: 1692 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19584897/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19584897&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19584897[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2009.103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19584897">Gazzerro et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19584897+30055862" 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 families diagnosed with LGMD1C, <a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> identified heterozygous mutations in the CAV3 gene: a missense mutation in the membrane-spanning region (P105L; <a href="#0001">601253.0001</a>) and a microdeletion in the scaffolding domain (<a href="#0002">601253.0002</a>). The mutations altered conserved invariant amino acid residues. <a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> predicted that these mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9537420" 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>Among 82 patients with muscular dystrophy of unknown genetic etiology, <a href="#25" class="mim-tip-reference" title="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> identified 1 female with a homozygous missense change in the CAV3 gene (G56S; <a href="#0003">601253.0003</a>). A second patient was identified with a heterozygous change on 1 allele (C72W; <a href="#0004">601253.0004</a>). Both mutations fall within a cytoplasmic region of caveolin-3 that had been implicated directly in inhibiting activity of neuronal nitric oxide synthase (NOS1; <a href="/entry/163731">163731</a>). NOS1 is part of the dystrophin-glycoprotein complex, and its association with the muscle membrane is altered in Duchenne muscular dystrophy (DMD; <a href="/entry/310200">310200</a>). Among 100 Brazilian normal control subjects without LGMD, <a href="#6" class="mim-tip-reference" title="de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. &lt;strong&gt;Mutations in the caveolin-3 gene: when are they pathogenic?&lt;/strong&gt; Am. J. Med. Genet. 99: 303-307, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11251997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11251997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(2001)9999:9999&lt;::aid-ajmg1168&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11251997">de Paula et al. (2001)</a> found 4 subjects who were heterozygous for the G55S change and 1 subject who was heterozygous for the C72W change. The authors concluded that the G56S and C72W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9536092+11251997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Herrmann, R., Straub, V., Blank, M., Kutzick, C., Franke, N., Jacob, E. N., Lenard, H.-G., Kroger, S., Voit, T. &lt;strong&gt;Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 9: 2335-2340, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11001938/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11001938&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/oxfordjournals.hmg.a018926&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11001938">Herrmann et al. (2000)</a> reported a 4-year-old girl presenting with myalgia and muscle cramps due to a heterozygous substitution in the caveolin-3 gene (A46T; <a href="#0005">601253.0005</a>) that prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan (DAG1; <a href="/entry/128239">128239</a>) expression was detected in the caveolin-3-deficient patient. The authors hypothesized common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies and caveolin-3-deficient limb-girdle muscular dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001938" 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="Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. &lt;strong&gt;Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia.&lt;/strong&gt; Neurology 54: 1373-1376, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10746614/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10746614&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.6.1373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10746614">Carbone et al. (2000)</a> identified a de novo recurrent sporadic mutation in the CAV3 gene (R27Q; <a href="#0007">601253.0007</a>) in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; <a href="/entry/123320">123320</a>) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. <a href="#4" class="mim-tip-reference" title="Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. &lt;strong&gt;Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia.&lt;/strong&gt; Neurology 54: 1373-1376, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10746614/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10746614&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.6.1373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10746614">Carbone et al. (2000)</a> concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746614" 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 5 families with autosomal dominant rippling muscle disease, <a href="#2" class="mim-tip-reference" title="Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. &lt;strong&gt;Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.&lt;/strong&gt; Nature Genet. 28: 218-219, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/90050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431690">Betz et al. (2001)</a> identified 4 missense mutations in the CAV3 gene (see, e.g., <a href="#0001">601253.0001</a>). They found that the same mutations in the CAV3 gene can give rise to rippling muscle disease and sporadic hyperCKemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431690" 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="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a> screened 663 patients with various phenotypes of unknown etiology (primarily clinical diagnoses of unclassified limb-girdle muscular dystrophy, hyperCKemia, and proximal myopathy), for caveolin-3 protein deficiency, and identified 8 caveolin-deficient patients from 7 families with CAV3 mutations. Four of the patients had the A46T mutation (<a href="#0005">601253.0005</a>). The authors noted the wide phenotypic and histologic variations in patients with the same mutation or from the same families, precluding a clear genotype/phenotype correlation. <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a> estimated that caveolinopathies represent 1% of both unclassified LGMD and other phenotypes, and demonstrated that caveolin-3 protein deficiencies are a highly sensitive and specific marker of primary caveolinopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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>Hypertrophic Cardiomyopathy and Long QT Syndrome</em></strong></p><p>
<a href="#18" class="mim-tip-reference" title="Hayashi, T., Arimura, T., Ueda, K., Shibata, H., Hohda, S., Takahashi, M., Hori, H., Koga, Y., Oka, N., Imaizumi, T., Yasunami, M., Kimura, A. &lt;strong&gt;Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 313: 178-184, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14672715/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14672715&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bbrc.2003.11.101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14672715">Hayashi et al. (2004)</a> examined the CAV3 gene for mutation in patients with hypertrophic cardiomyopathy (CMH; <a href="/entry/192600">192600</a>) or dilated cardiomyopathy. They found a thr64-to-ser mutation (<a href="#0013">601253.0013</a>) in 2 brothers with hypertrophic cardiomyopathy but not in their mother, who did not show left ventricular hypertrophy. Thus, it was suggested that the mutation had been inherited from their father, but this could not be confirmed since the father, who was also affected with hypertrophic cardiomyopathy, had died suddenly at the age of 41 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14672715" 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="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. &lt;strong&gt;Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.&lt;/strong&gt; Circulation 114: 2104-2112, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17060380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17060380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCULATIONAHA.106.635268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17060380">Vatta et al. (2006)</a> analyzed the CAV3 gene in 905 unrelated patients with long QT syndrome who had previously been tested for mutations in known LQT genes and identified 4 heterozygous missense mutations in 6 patients (<a href="#0016">601253.0016</a>-<a href="#0019">601253.0019</a>, respectively) with LQT9 (<a href="/entry/611818">611818</a>). The mutations were not found in more than 1,000 control alleles. Electrophysiologic analysis of transiently transfected HEK293 cells stably expressing the cardiac sodium channel demonstrated that the mutant caveolin-3 resulted in a 2- to 3-fold increase in the late sodium current compared with wildtype caveolin-3. One patient had biallelic digenic mutations, with a missense mutation in the LQT2 (<a href="/entry/613688">613688</a>)-associated KCNH2 gene (<a href="/entry/152427">152427</a>) as well as in the CAV3 gene (see <a href="#0018">601253.0018</a> and <a href="/entry/152427#0024">152427.0024</a>) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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>Sudden Infant Death Syndrome</em></strong></p><p>
<a href="#5" class="mim-tip-reference" title="Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. &lt;strong&gt;Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.&lt;/strong&gt; Heart Rhythm 4: 161-166, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17275750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17275750&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17275750[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.hrthm.2006.11.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17275750">Cronk et al. (2007)</a> analyzed the CAV3 gene in necropsy tissue from 134 unrelated cases of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>) and identified 3 missense mutations in 3 of 50 black infants (<a href="#0018">601253.0018</a>; <a href="#0020">601253.0020</a>; and <a href="#0021">601253.0021</a>). No mutations were detected in 1 Hispanic or 83 white infants. Voltage-clamp studies demonstrated a gain-of-function phenotype for all 3 CAV3 mutations, with a 5-fold increase in late sodium current compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275750" 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="#16" class="mim-tip-reference" title="Hagiwara, Y., Sasaoka, T., Araishi, K., Imamura, M., Yorifuji, H., Nonaka, I., Ozawa, E., Kikuchi, T. &lt;strong&gt;Caveolin-3 deficiency causes muscle degeneration in mice.&lt;/strong&gt; Hum. Molec. Genet. 9: 3047-3054, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11115849/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11115849&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.20.3047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11115849">Hagiwara et al. (2000)</a> developed caveolin-3-deficient mice for use as animal models of caveolinopathy. Caveolin-3 mRNA and its protein were absent in homozygous mutant mice. Muscle degeneration was recognized in soleus muscle at 8 weeks of age and in the diaphragm from 8 to 30 weeks, although there was no difference in growth and movement between wildtype and mutant mice. No apparent muscle degeneration was observed in heterozygous mutant mice, consistent with autosomal recessive transmission of the phenotype. This is in contrast to the dominant-negative acting missense mutations found in human LGMD1C. Note that LGMD1C has been reclassified as RMD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115849" 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>Duchenne muscular dystrophy patients and mdx mice show elevated levels of caveolin-3 expression in skeletal muscle. To investigate whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of the disorder, <a href="#11" class="mim-tip-reference" title="Galbiati, F., Volonte, D., Chu, J. B., Li, M., Fine, S. W., Fu, M., Bermudez, J., Pedemonte, M., Weidenheim, K. M., Pestell, R. G., Minetti, C., Lisanti, M. P. &lt;strong&gt;Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 9689-9694, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10931944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10931944&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10931944[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.160249097&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10931944">Galbiati et al. (2000)</a> overexpressed wildtype caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3-overexpressing transgenic mice showed a dramatic increase in the number of sarcolemmal muscle cell caveolae; a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and downregulation of dystrophin and beta-dystroglycan protein expression. In addition, the mice showed elevated serum creatine kinase levels, consistent with the myonecrosis observed morphologically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10931944" 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="Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T. &lt;strong&gt;Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity.&lt;/strong&gt; Hum. Molec. Genet. 10: 173-178, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11159934/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11159934&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.3.173&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11159934">Sunada et al. (2001)</a> generated transgenic mice expressing the pro105-to-leu mutant caveolin-3 (P105L; <a href="#0001">601253.0001</a>). Mice showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, suggesting a dominant-negative effect of mutant caveolin-3. Caveolin-3 had been shown to interact with neuronal nitric oxide synthase (nNOS; <a href="/entry/163731">163731</a>) and inhibit its catalytic activity (<a href="#13" class="mim-tip-reference" title="Garcia-Cardena, G., Martasek, P., Masters, B. S. S., Skidd, P. M., Couet, J. C., Li, S., Lisanti, M. P., Sessa, W. C. &lt;strong&gt;Dissecting the interaction between nitric oxide synthase (NOS) and caveolin: functional significance of the NOS caveolin binding domain in vivo.&lt;/strong&gt; J. Biol. Chem. 272: 25437-25440, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9325253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9325253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.272.41.25437&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9325253">Garcia-Cardena et al., 1997</a>). <a href="#36" class="mim-tip-reference" title="Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T. &lt;strong&gt;Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity.&lt;/strong&gt; Hum. Molec. Genet. 10: 173-178, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11159934/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11159934&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.3.173&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11159934">Sunada et al. (2001)</a> found a great increase of nNOS activity in the transgenic skeletal muscle, suggesting a role for nitric oxide synthase in muscle fiber degeneration in caveolin-3 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9325253+11159934" 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="Aravamudan, B., Volonte, D., Ramani, R., Gursoy, E., Lisanti, M. P., London, B., Galbiati, F. &lt;strong&gt;Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype.&lt;/strong&gt; Hum. Molec. Genet. 12: 2777-2788, 2003. Note: Erratum: Hum. Molec. Genet. 13: 149 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12966035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12966035&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg313&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12966035">Aravamudan et al. (2003)</a> showed that Cav3-overexpressing transgenic mice had severe cardiac tissue degeneration, fibrosis, and a reduction in cardiac functions. Dystrophin and its associated glycoproteins were downregulated in Cav3 transgenic hearts. In addition, the activity of nitric oxide synthase was downregulated by high levels of caveolin-3 in the heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966035" 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>Caveolin-3 binds to eNOS (NOS3; <a href="/entry/163729">163729</a>) in cardiac myocytes and nNOS in skeletal myocytes. <a href="#31" class="mim-tip-reference" title="Ohsawa, Y., Toko, H., Katsura, M., Morimoto, K., Yamada, H., Ichikawa, Y., Murakami, T., Ohkuma, S., Komuro, I., Sunada, Y. &lt;strong&gt;Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.&lt;/strong&gt; Hum. Molec. Genet. 13: 151-157, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14645200/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14645200&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14645200">Ohsawa et al. (2004)</a> characterized the biochemical and cardiac parameters of P105L mutant mice, a model of LGMD1C (RMD2). Transgenic mouse hearts demonstrated hypertrophic cardiomyopathy, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of Cav3 protein. Cardiac muscle showed activation of eNOS catalytic activity without increased expression of all NOS isoforms. <a href="#31" class="mim-tip-reference" title="Ohsawa, Y., Toko, H., Katsura, M., Morimoto, K., Yamada, H., Ichikawa, Y., Murakami, T., Ohkuma, S., Komuro, I., Sunada, Y. &lt;strong&gt;Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.&lt;/strong&gt; Hum. Molec. Genet. 13: 151-157, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14645200/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14645200&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14645200">Ohsawa et al. (2004)</a> suggested that a moderate increase in eNOS activity associated with loss of Cav3 may result in hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645200" 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="Oshikawa, J., Otsu, K., Toya, Y., Tsunematsu, T., Hankins, R., Kawabe, J., Minamisawa, S., Umemura, S., Hagiwara, Y., Ishikawa, Y. &lt;strong&gt;Insulin resistance in skeletal muscles of caveolin-3-null mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 101: 12670-12675, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15314230/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15314230&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15314230[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0402053101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15314230">Oshikawa et al. (2004)</a> examined the role of Cav3 in insulin signaling in a strain of Cav3 knockout mice originally developed as a model of DMD. They found Cav3 knockout led to the development of insulin resistance, as shown by decreased glucose uptake in skeletal muscles, impaired glucose tolerance, and increased serum lipids. Impairments were augmented in the presence of streptozotocin, a pancreatic beta cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of insulin receptors (INSR; <a href="/entry/147670">147670</a>) and downstream molecules, such as Irs1 (<a href="/entry/147545">147545</a>) and Akt (see AKT1; <a href="/entry/164730">164730</a>), was attenuated in the skeletal muscle of Cav3-null mice, but not in liver, without affecting Insr expression or subcellular localization. Cav3 gene transfer restored insulin signaling in skeletal muscles. <a href="#32" class="mim-tip-reference" title="Oshikawa, J., Otsu, K., Toya, Y., Tsunematsu, T., Hankins, R., Kawabe, J., Minamisawa, S., Umemura, S., Hagiwara, Y., Ishikawa, Y. &lt;strong&gt;Insulin resistance in skeletal muscles of caveolin-3-null mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 101: 12670-12675, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15314230/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15314230&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15314230[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0402053101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15314230">Oshikawa et al. (2004)</a> concluded that CAV3 is an enhancer of insulin signaling in skeletal muscle but it does not act as a scaffolding molecule for INSR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15314230" 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="Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G. &lt;strong&gt;Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning.&lt;/strong&gt; Hum. Molec. Genet. 14: 1727-1743, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15888488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15888488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi179&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15888488">Nixon et al. (2005)</a> showed that in zebrafish embryonic development Cav3 and caveolae were located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan (DAG1; <a href="/entry/128239">128239</a>) was restricted to the muscle fiber ends. Downregulation of Cav3 expression caused gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers revealed defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3 P105L (<a href="#0001">601253.0001</a>), caused severe disruption of muscle differentiation. Knockdown of Cav3 resulted in a dramatic upregulation of Eng1a (see EN1; <a href="/entry/131290">131290</a>) expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. <a href="#29" class="mim-tip-reference" title="Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G. &lt;strong&gt;Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning.&lt;/strong&gt; Hum. Molec. Genet. 14: 1727-1743, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15888488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15888488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi179&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15888488">Nixon et al. (2005)</a> concluded that Cav3 is essential to muscle development, particularly for correct intracellular organization and myoblast fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888488" 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 COS-7 cells, <a href="#30" class="mim-tip-reference" title="Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. &lt;strong&gt;Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.&lt;/strong&gt; J. Clin. Invest. 116: 2924-2934, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17039257/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17039257&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI28520&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17039257">Ohsawa et al. (2006)</a> found that caveolin-3 inhibited signaling of myostatin (MSTN; <a href="/entry/601788">601788</a>), a molecule that negatively regulates skeletal muscle volume by direct interaction with and inhibition of the type I myostatin receptors ALK4 (<a href="/entry/601300">601300</a>) and ALK5 (<a href="/entry/190181">190181</a>). Doubly transgenic mice with both Cav3 deficiency and myostatin inhibition showed increased numbers and size of myofibers compared to singly Cav3-deficient mice, effectively reversing the muscle atrophy induced by Cav3 deficiency. In addition, intraperitoneal injection of a myostatin inhibitor improved functional muscle weakness in Cav3-deficient mice. <a href="#30" class="mim-tip-reference" title="Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. &lt;strong&gt;Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.&lt;/strong&gt; J. Clin. Invest. 116: 2924-2934, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17039257/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17039257&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI28520&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17039257">Ohsawa et al. (2006)</a> suggested that caveolin-3 normally suppresses myostatin signaling and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in this mouse model of LGMD1C (RMD2). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17039257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Kuga, A., Ohsawa, Y., Okada, T., Kanda, F., Kanagawa, M., Toda, T., Sunada, Y. &lt;strong&gt;Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice.&lt;/strong&gt; Hum. Molec. Genet. 20: 2975-2983, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21610159/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21610159&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddr201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21610159">Kuga et al. (2011)</a> found that Cav3(P104L) accumulated in the Golgi apparatus of transgenic mice and in transfected COS-7 cells. Use of wildtype and hemizygous and homozygous Cav3(P104L) mutant mice revealed a dose-dependent induction of the endoplasmic reticulum stress response by Cav3(P104L), including upregulation of the molecular chaperone Gpr78 (HSPA5; <a href="/entry/138120">138120</a>) and a mild apoptotic skeletal muscle phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610159" 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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&nbsp;&nbsp;<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601253[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<a id="0001" class="mim-anchor"></a>
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<strong>.0001&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, PRO105LEU
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840805;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=rs116840805" 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=rs116840805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008765 OR RCV000024379 OR RCV005089211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008765, RCV000024379, RCV005089211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008765...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation PRO104LEU. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 4 members over 2 generations of an Italian family diagnosed with limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> identified a heterozygous 311C-to-T transition in the CAV3 gene, resulting in a pro104-to-leu (P104L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30055862+9537420" 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 family A with rippling muscle disease described by <a href="#33" class="mim-tip-reference" title="Ricker, K., Moxley, R. T., Rohkamm, R. &lt;strong&gt;Rippling muscle disease.&lt;/strong&gt; Arch. Neurol. 46: 405-408, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2705900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2705900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1989.00520400065020&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2705900">Ricker et al. (1989)</a>, <a href="#2" class="mim-tip-reference" title="Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. &lt;strong&gt;Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.&lt;/strong&gt; Nature Genet. 28: 218-219, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/90050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431690">Betz et al. (2001)</a> identified the P105L mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431690+2705900" 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>Variant Function</em></strong></p><p>
<a href="#12" class="mim-tip-reference" title="Galbiati, F., Volonte, D., Minetti, C., Chu, J. B., Lisanti, M. P. &lt;strong&gt;Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C): retention of LGMD-1C caveolin-3 mutants within the Golgi complex.&lt;/strong&gt; J. Biol. Chem. 274: 25632-25641, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10464299/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10464299&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.274.36.25632&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10464299">Galbiati et al. (1999)</a> stated that P104 resides in the membrane-spanning domain of CAV3. They found that rat Cav3 with the P104L mutation was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10464299" 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="0002" class="mim-anchor"></a>
<h4>
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<strong>.0002&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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</h4>
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<span class="mim-text-font">
<div style="float: left;">
CAV3, 9-BP DEL, NT186
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840800 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840800;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=rs116840800" 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=rs116840800" 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">rs199476331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476331;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=rs199476331" 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=rs199476331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008767 OR RCV000024380" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008767, RCV000024380" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008767...</a>
</span>
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<div>
<span class="mim-text-font">
<p><a href="#28" class="mim-tip-reference" title="Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. &lt;strong&gt;Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.&lt;/strong&gt; Nature Genet. 18: 365-368, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9537420/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9537420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0498-365&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9537420">Minetti et al. (1998)</a> demonstrated that 4 affected members in 3 generations of an Italian family diagnosed with autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), had a 9-bp deletion beginning at nucleotide 186 of the CAV3 gene, which resulted in the loss of 3 amino acids (residues 63-65) without changing the open reading frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30055862+9537420" 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>Variant Function</em></strong></p><p>
<a href="#12" class="mim-tip-reference" title="Galbiati, F., Volonte, D., Minetti, C., Chu, J. B., Lisanti, M. P. &lt;strong&gt;Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C): retention of LGMD-1C caveolin-3 mutants within the Golgi complex.&lt;/strong&gt; J. Biol. Chem. 274: 25632-25641, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10464299/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10464299&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.274.36.25632&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10464299">Galbiati et al. (1999)</a> stated that the residues lost in this deletion (TFT) reside within the caveolin scaffolding domain. They found that rat Cav3 with the TFT deletion was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10464299" 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="0003" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0003&nbsp;RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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<span class="mim-text-font">
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CAV3, GLY56SER
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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">&#x25cf;</span> rs72546667 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72546667;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/rs72546667?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs72546667" 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=rs72546667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008768 OR RCV000039799 OR RCV000119393 OR RCV000171805 OR RCV000249765 OR RCV000362621 OR RCV000987086 OR RCV001082614 OR RCV001150159 OR RCV001171080 OR RCV002496306" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008768, RCV000039799, RCV000119393, RCV000171805, RCV000249765, RCV000362621, RCV000987086, RCV001082614, RCV001150159, RCV001171080, RCV002496306" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008768...</a>
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<p>This variant, formerly titled MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, AUTOSOMAL RECESSIVE, has been reclassified as a variant of unknown significance based on the findings by <a href="#6" class="mim-tip-reference" title="de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. &lt;strong&gt;Mutations in the caveolin-3 gene: when are they pathogenic?&lt;/strong&gt; Am. J. Med. Genet. 99: 303-307, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11251997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11251997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(2001)9999:9999&lt;::aid-ajmg1168&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11251997">de Paula et al. (2001)</a> and <a href="#17" class="mim-tip-reference" title="Hamosh, A. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. January 24, 2018."None>Hamosh (2018)</a>. Note that limb-girdle muscular dystrophy (LGMD1C) was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11251997+30055862" 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 numbering of this CAV3 mutation (G56S) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation GLY55SER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> found homozygosity for a gly55-to-ser change (G55S) in 1 of 82 patients with muscular dystrophy screened for mutations in the CAV3 gene. This patient was the only affected member of her family, and developed proximal muscle weakness in the first decade. The mutation was not identified in 200 control chromosomes. Expression of dystrophin, the sarcoglycans, and caveolin-3 was grossly normal in a skeletal muscle biopsy from the patient, and the authors suggested that the G55S change may not alter the intracellular location of the protein, yet may interfere with the normal function of the protein in the membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536092" 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>Among 61 Brazilian patients diagnosed with LGMD, <a href="#6" class="mim-tip-reference" title="de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. &lt;strong&gt;Mutations in the caveolin-3 gene: when are they pathogenic?&lt;/strong&gt; Am. J. Med. Genet. 99: 303-307, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11251997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11251997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(2001)9999:9999&lt;::aid-ajmg1168&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11251997">de Paula et al. (2001)</a> identified 2 patients with a heterozygous G55S mutation. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening of 200 normal Brazilian chromosomes revealed heterozygosity for the G55S change in 4 subjects and for a C71W change (<a href="#0004">601253.0004</a>) in 1 subject. The authors concluded that the G55S and C71W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. The abnormal phenotype in the 2 patients is likely caused by mutation in another LGMD gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11251997" 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="Hamosh, A. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. January 24, 2018."None>Hamosh (2018)</a> found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant.</p>
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<strong>.0004&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, CYS72TRP
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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">&#x25cf;</span> rs116840776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840776;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/rs116840776?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs116840776" 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=rs116840776" 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=RCV000008769 OR RCV000024381 OR RCV000150236 OR RCV000171752 OR RCV000249612 OR RCV000477819 OR RCV000769171 OR RCV000987087 OR RCV001084478 OR RCV001144018 OR RCV003952349" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008769, RCV000024381, RCV000150236, RCV000171752, RCV000249612, RCV000477819, RCV000769171, RCV000987087, RCV001084478, RCV001144018, RCV003952349" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008769...</a>
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<p>The numbering of this CAV3 mutation (C72W) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation CYS71TRP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 1 of 82 patients with muscular dystrophy (see RMD2; <a href="/entry/606072">606072</a>), <a href="#25" class="mim-tip-reference" title="McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. &lt;strong&gt;Caveolin-3 in muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 7: 871-877, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9536092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9536092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.5.871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9536092">McNally et al. (1998)</a> identified a heterozygous C-to-G change in the CAV3 gene, resulting in a cys71-to-trp (C71W) substitution. The patient had progressive proximal muscle weakness beginning in the first decade, but remained ambulatory in the mid-second decade. Her mother and 2 siblings had the identical missense change, but did not have symptoms of muscular dystrophy, suggesting that a single abnormal allele is not sufficient to cause the phenotype and that the likely inheritance is autosomal recessive. The authors were unable to determine the nature of the second allele in the proband. The mutation was not identified in 200 control chromosomes. <a href="#26" class="mim-tip-reference" title="McNally, E. M. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Chicago, Ill. 6/8/1998."None>McNally (1998)</a> suspected that the phenotype was the result of either loss-of-function mutations or dominant-negative mutations; she doubted that haploinsufficiency leads to the disease. The family was lost to follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536092" 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>Among 100 normal Brazilian control subjects, <a href="#6" class="mim-tip-reference" title="de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. &lt;strong&gt;Mutations in the caveolin-3 gene: when are they pathogenic?&lt;/strong&gt; Am. J. Med. Genet. 99: 303-307, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11251997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11251997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(2001)9999:9999&lt;::aid-ajmg1168&gt;3.0.co;2-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11251997">de Paula et al. (2001)</a> identified heterozygosity for the C71W change in 1 subject. They concluded that C71W is a rare polymorphism that does not cause an abnormal phenotype when present in just one allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11251997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED
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CAV3, ALA46THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840789 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840789;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=rs116840789" 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=rs116840789" 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=RCV000008772 OR RCV000008774 OR RCV000024382 OR RCV001384920 OR RCV002381245 OR RCV004585993" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008772, RCV000008774, RCV000024382, RCV001384920, RCV002381245, RCV004585993" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008772...</a>
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<p>The numbering of this CAV3 mutation (A46T) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation ALA45THR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 4-year-old girl presenting with myalgia and muscle cramps diagnosed as limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#19" class="mim-tip-reference" title="Herrmann, R., Straub, V., Blank, M., Kutzick, C., Franke, N., Jacob, E. N., Lenard, H.-G., Kroger, S., Voit, T. &lt;strong&gt;Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.&lt;/strong&gt; Hum. Molec. Genet. 9: 2335-2340, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11001938/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11001938&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/oxfordjournals.hmg.a018926&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11001938">Herrmann et al. (2000)</a> identified a heterozygous 136G-to-A change, resulting in an ala46-to-thr substitution. The mutation prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30055862+11001938" 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 families with rippling muscle disease from Germany, reported by <a href="#41" class="mim-tip-reference" title="Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W. &lt;strong&gt;Phenotypic variability in rippling muscle disease.&lt;/strong&gt; Neurology 52: 1453-1459, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10227634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10227634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.52.7.1453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10227634">Vorgerd et al. (1999)</a>, and the first-described RMD family from Norway, reported by <a href="#39" class="mim-tip-reference" title="Torbergsen, T. &lt;strong&gt;A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita Thomsen.&lt;/strong&gt; Acta Neurol. Scand. 51: 225-232, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1146501/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1146501&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-0404.1975.tb07603.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1146501">Torbergsen (1975)</a>, <a href="#2" class="mim-tip-reference" title="Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. &lt;strong&gt;Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.&lt;/strong&gt; Nature Genet. 28: 218-219, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/90050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431690">Betz et al. (2001)</a> identified a heterozygous mutation in the CAV3 gene, resulting in an ala45-to-thr substitution (A45T). A muscle biopsy from a patient carrying the mutation showed decreased surface expression of the caveolin-3 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431690+1146501+10227634" 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="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a> identified the A46T mutation in 4 unrelated patients with decreased caveolin-3 on muscle biopsy. Three patients had myalgia and/or mild proximal muscle weakness, whereas 1 was diagnosed with LGMD1C. Three of the patients had a positive family history of muscle-related disorders. The father and 2 paternal uncles of 1 patient with mild muscle weakness were reportedly asymptomatic with elevated serum creatine kinase (<a href="/entry/123320">123320</a>). Skeletal muscle caveolin-3 protein in the 4 probands ranged from less than 5 to 10%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, ALA46VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840773 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840773;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=rs116840773" 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=rs116840773" 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=RCV000008775 OR RCV000024383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008775, RCV000024383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008775...</a>
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<p>The numbering of this CAV3 mutation (A46V) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation ALA45VAL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 family B with rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>) described by <a href="#33" class="mim-tip-reference" title="Ricker, K., Moxley, R. T., Rohkamm, R. &lt;strong&gt;Rippling muscle disease.&lt;/strong&gt; Arch. Neurol. 46: 405-408, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2705900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2705900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1989.00520400065020&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2705900">Ricker et al. (1989)</a>, <a href="#2" class="mim-tip-reference" title="Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. &lt;strong&gt;Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.&lt;/strong&gt; Nature Genet. 28: 218-219, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/90050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431690">Betz et al. (2001)</a> identified a mutation in the CAV3 gene, resulting in an ala45-to-val (A45V) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431690+2705900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED<br />
MYOPATHY, DISTAL, TATEYAMA TYPE, INCLUDED
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CAV3, ARG27GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840778 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840778;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=rs116840778" 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=rs116840778" 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=RCV000008777 OR RCV000008778 OR RCV000023083 OR RCV000408119 OR RCV000527324 OR RCV002490340" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008777, RCV000008778, RCV000023083, RCV000408119, RCV000527324, RCV002490340" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008777...</a>
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<p>The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation ARG26GLN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 kindred B with autosomal dominant rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>) described by <a href="#41" class="mim-tip-reference" title="Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W. &lt;strong&gt;Phenotypic variability in rippling muscle disease.&lt;/strong&gt; Neurology 52: 1453-1459, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10227634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10227634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.52.7.1453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10227634">Vorgerd et al. (1999)</a>, <a href="#2" class="mim-tip-reference" title="Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. &lt;strong&gt;Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.&lt;/strong&gt; Nature Genet. 28: 218-219, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11431690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/90050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11431690">Betz et al. (2001)</a> identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431690+10227634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with sporadic rippling muscle disease, <a href="#42" class="mim-tip-reference" title="Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W. &lt;strong&gt;A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.&lt;/strong&gt; Neurology 57: 2273-2277, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11756609/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11756609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.57.12.2273&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11756609">Vorgerd et al. (2001)</a> identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. <a href="#42" class="mim-tip-reference" title="Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W. &lt;strong&gt;A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.&lt;/strong&gt; Neurology 57: 2273-2277, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11756609/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11756609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.57.12.2273&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11756609">Vorgerd et al. (2001)</a> suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11756609" 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 71-year-old woman with a diagnosis of limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#8" class="mim-tip-reference" title="Figarella-Branger, D., Pouget, J., Bernard, R., Krahn, M., Fernandez, C., Levy, N., Pellissier, J. F. &lt;strong&gt;Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene.&lt;/strong&gt; Neurology 61: 562-564, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12939441/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12939441&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000076486.57572.5c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12939441">Figarella-Branger et al. (2003)</a> identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. <a href="#8" class="mim-tip-reference" title="Figarella-Branger, D., Pouget, J., Bernard, R., Krahn, M., Fernandez, C., Levy, N., Pellissier, J. F. &lt;strong&gt;Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene.&lt;/strong&gt; Neurology 61: 562-564, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12939441/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12939441&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000076486.57572.5c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12939441">Figarella-Branger et al. (2003)</a> emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30055862+12939441" 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="Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. &lt;strong&gt;Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia.&lt;/strong&gt; Neurology 54: 1373-1376, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10746614/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10746614&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.6.1373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10746614">Carbone et al. (2000)</a> identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; <a href="/entry/123320">123320</a>) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. <a href="#4" class="mim-tip-reference" title="Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. &lt;strong&gt;Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia.&lt;/strong&gt; Neurology 54: 1373-1376, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10746614/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10746614&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.6.1373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10746614">Carbone et al. (2000)</a> concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746614" 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 Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; <a href="/entry/614321">614321</a>), <a href="#38" class="mim-tip-reference" title="Tateyama, M., Aoki, M., Nishino, I., Hayashi, Y. K., Sekiguchi, S., Shiga, Y., Takahashi, T., Onodera, Y., Haginoya, K., Kobayashi, K., Iinuma, K., Nonaka, I., Arahata, K., Itoyama, Y. &lt;strong&gt;Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.&lt;/strong&gt; Neurology 58: 323-325, 2002. Note: Erratum: Neurology 58: 839 only, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11805270/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11805270&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.58.2.323&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11805270">Tateyama et al. (2002)</a> identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin (<a href="/entry/603009">603009</a>) immunoreactivity. <a href="#38" class="mim-tip-reference" title="Tateyama, M., Aoki, M., Nishino, I., Hayashi, Y. K., Sekiguchi, S., Shiga, Y., Takahashi, T., Onodera, Y., Haginoya, K., Kobayashi, K., Iinuma, K., Nonaka, I., Arahata, K., Itoyama, Y. &lt;strong&gt;Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.&lt;/strong&gt; Neurology 58: 323-325, 2002. Note: Erratum: Neurology 58: 839 only, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11805270/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11805270&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.58.2.323&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11805270">Tateyama et al. (2002)</a> noted the unusual clinical phenotype of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11805270" 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="Gonzalez-Perez, P., Gallano, P., Gonzalez-Quereda, L., Rivas-Infante, E., Teijeira, S., Navarro, C., Bautista-Lorite, J. &lt;strong&gt;Phenotypic variability in a Spanish family with a caveolin-3 mutation.&lt;/strong&gt; J. Neurol. Sci. 276: 95-98, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18930476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18930476&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jns.2008.09.009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18930476">Gonzalez-Perez et al. (2009)</a> identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. <a href="#15" class="mim-tip-reference" title="Gonzalez-Perez, P., Gallano, P., Gonzalez-Quereda, L., Rivas-Infante, E., Teijeira, S., Navarro, C., Bautista-Lorite, J. &lt;strong&gt;Phenotypic variability in a Spanish family with a caveolin-3 mutation.&lt;/strong&gt; J. Neurol. Sci. 276: 95-98, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18930476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18930476&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jns.2008.09.009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18930476">Gonzalez-Perez et al. (2009)</a> noted the variable phenotypic features in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18930476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, ASP28GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840782 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840782;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=rs116840782" 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=rs116840782" 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=RCV000008770 OR RCV000024386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008770, RCV000024386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008770...</a>
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<p>The numbering of this CAV3 mutation (D28E) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation ASP27GLU. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 9 affected members of a large German family with autosomal dominant rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#9" class="mim-tip-reference" title="Fischer, D., Schroers, A., Blumcke, I., Urbach, H., Zerres, K., Mortier, W., Vorgerd, M., Schroder, R. &lt;strong&gt;Consequences of a novel caveolin-3 mutation in a large German family.&lt;/strong&gt; Ann. Neurol. 53: 233-241, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12557291/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12557291&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12557291">Fischer et al. (2003)</a> identified a heterozygous C-A change in exon 1 of the CAV3 gene, resulting in an asp27-to-glu (D27E) substitution within the N terminus of the protein. The mutation was not detected in 10 unaffected family members or in 200 normal control chromosomes. Five of the 9 patients had additional signs of a distal myopathy with ankle and hand weakness and atrophy. Two other patients had predominantly proximal muscle weakness and were diagnosed with limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease. The 2 youngest patients showed only isolated signs of rippling muscle disease without muscle weakness or atrophy. Immunohistochemical and Western blot analysis showed a severe reduction of CAV3 protein expression in skeletal muscle from the index patient, supporting a dominant-negative effect of the mutation. The authors commented on the marked intrafamilial clinical variability caused by the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12557291+30055862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, LEU87PRO
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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">&#x25cf;</span> rs28936685 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936685;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/rs28936685?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28936685" 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=rs28936685" 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=RCV000008779 OR RCV000024387 OR RCV000458893 OR RCV001787372 OR RCV003352748" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008779, RCV000024387, RCV000458893, RCV001787372, RCV003352748" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008779...</a>
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<p>The numbering of this CAV3 mutation (L87P) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation LEU86PRO. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 Colombian patient with severe rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#21" class="mim-tip-reference" title="Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. &lt;strong&gt;Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.&lt;/strong&gt; Ann. Neurol. 53: 512-520, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12666119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12666119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12666119">Kubisch et al. (2003)</a> identified a homozygous 215T-C transition in the CAV3 gene, resulting in a leu86-to-pro substitution (L86P) in the membrane-associated domain of the protein. The patient had muscle stiffness in his legs since the age of 3 years and contractures of the Achilles tendon leading to gait disturbances. At age 20, he had elevated creatine kinase levels, hypertrophic skeletal muscles, and generalized rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin (<a href="/entry/603009">603009</a>). The patient did not have family members available for further study, so it could not be determined if the mutation represented autosomal recessive RMD. <a href="#21" class="mim-tip-reference" title="Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. &lt;strong&gt;Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.&lt;/strong&gt; Ann. Neurol. 53: 512-520, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12666119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12666119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12666119">Kubisch et al. (2003)</a> noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies are part of a clinical continuum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12666119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010&nbsp;RIPPLING MUSCLE DISEASE 2, AUTOSOMAL RECESSIVE</strong>
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CAV3, ALA93THR
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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">&#x25cf;</span> rs28936686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936686;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/rs28936686?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28936686" 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=rs28936686" 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=RCV000008780 OR RCV000024388 OR RCV000234612 OR RCV000622234 OR RCV000826098 OR RCV005031426" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008780, RCV000024388, RCV000234612, RCV000622234, RCV000826098, RCV005031426" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008780...</a>
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<p>The numbering of this CAV3 mutation (A93T) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation ALA92THR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 an Italian patient with severe rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#21" class="mim-tip-reference" title="Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. &lt;strong&gt;Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.&lt;/strong&gt; Ann. Neurol. 53: 512-520, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12666119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12666119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12666119">Kubisch et al. (2003)</a> identified a homozygous 232G-A transition in the CAV3 gene, resulting in an ala92-to-thr substitution (A92T) in the membrane-associated domain of the protein. The patient had slowly progressive muscle weakness beginning in early adulthood, elevated creatine kinase, and rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin (<a href="/entry/603009">603009</a>). <a href="#21" class="mim-tip-reference" title="Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. &lt;strong&gt;Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.&lt;/strong&gt; Ann. Neurol. 53: 512-520, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12666119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12666119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12666119">Kubisch et al. (2003)</a> noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies are part of a clinical continuum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12666119" 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="Kubisch, C., Ketelsen, U.-P., Goebel, I., Omran, H. &lt;strong&gt;Autosomal recessive rippling muscle disease with homozygous CAV3 mutations. (Letter)&lt;/strong&gt; Ann. Neurol. 57: 303-304, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15668980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15668980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20350&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15668980">Kubisch et al. (2005)</a> identified homozygosity for the A92T mutation in 2 German sibs with childhood-onset of rippling muscle disease. Both unaffected parents were heterozygous for the mutation. The findings indicated that there is a form of autosomal recessive RMD in which heterozygous carriers do not manifest the disease. Haplotype analysis indicated that the mutation arose independently from the mutation observed in the Italian patient reported by <a href="#21" class="mim-tip-reference" title="Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. &lt;strong&gt;Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.&lt;/strong&gt; Ann. Neurol. 53: 512-520, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12666119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12666119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12666119">Kubisch et al. (2003)</a>, suggesting that A92T is a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15668980+12666119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011&nbsp;CREATINE PHOSPHOKINASE, ELEVATED SERUM</strong>
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RIPPLING MUSCLE DISEASE 2, INCLUDED
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CAV3, 3-BP DEL, PHE98DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840802 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840802;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=rs116840802" 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=rs116840802" 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">rs199476335 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476335;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=rs199476335" 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=rs199476335" 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=RCV000008781 OR RCV000008782 OR RCV000024390 OR RCV004786247" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008781, RCV000008782, RCV000024390, RCV004786247" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008781...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation PHE97DEL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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="Cagliani, R., Bresolin, N., Prelle, A., Gallanti, A., Fortunato, F., Sironi, M., Ciscato, P., Fagiolari, G., Bonato, S., Galbiati, S., Corti, S., Lamperti, C., Moggio, M., Comi, G. P. &lt;strong&gt;A CAV3 microdeletion differentially affects skeletal muscle and myocardium.&lt;/strong&gt; Neurology 61: 1513-1519, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14663034/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14663034&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000097320.35982.03&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14663034">Cagliani et al. (2003)</a> reported a multigenerational Italian family with deletion of nucleotides 328-330 in the CAV3 gene, resulting in deletion of phenylalanine at codon 97. All members with the mutation had elevated serum creatine kinase (<a href="/entry/123320">123320</a>), but there was remarkable intrafamilial variation in other features, including rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), proximal limb weakness, distal limb weakness, and what was considered to be a more severe limb-girdle muscular dystrophy (LGMD1C), which was reclassified by <a href="#35" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. &lt;strong&gt;229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.&lt;/strong&gt; Neuromusc. Disord. 28: 702-710, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30055862/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30055862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2018.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30055862">Straub et al. (2018)</a> as rippling muscle disease. Muscle biopsy of 3 affected patients showed myopathic changes and a deficiency of caveolin-3 by immunostaining and Western blot analysis. A heart biopsy in 1 patient showed that caveolin-3 was present at approximately 60% of the normal level. <a href="#3" class="mim-tip-reference" title="Cagliani, R., Bresolin, N., Prelle, A., Gallanti, A., Fortunato, F., Sironi, M., Ciscato, P., Fagiolari, G., Bonato, S., Galbiati, S., Corti, S., Lamperti, C., Moggio, M., Comi, G. P. &lt;strong&gt;A CAV3 microdeletion differentially affects skeletal muscle and myocardium.&lt;/strong&gt; Neurology 61: 1513-1519, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14663034/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14663034&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000097320.35982.03&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14663034">Cagliani et al. (2003)</a> noted that the findings provided an explanation of why heart involvement is not a feature of caveolinopathies, and suggested that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14663034+30055862" 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&nbsp;CREATINE PHOSPHOKINASE, ELEVATED SERUM</strong>
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CAV3, PRO29LEU
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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">&#x25cf;</span> rs116840786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840786;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/rs116840786?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs116840786" 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=rs116840786" 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=RCV000008784 OR RCV000024389 OR RCV003531900" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008784, RCV000024389, RCV003531900" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008784...</a>
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<p>The numbering of this CAV3 mutation (P29L) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation PRO28LEU. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 an 18-year-old man and his mother with isolated persistent hyperCKemia (<a href="/entry/123320">123320</a>), <a href="#27" class="mim-tip-reference" title="Merlini, L., Carbone, I., Capanni, C., Sabatelli, P., Tortorelli, S., Sotgia, F., Lisanti, M. P., Bruno, C., Minetti, C. &lt;strong&gt;Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 73: 65-67, 2002. Note: Erratum: J. Neurol. Neurosurg. Psychiat. 74: 142 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12082049/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12082049&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.73.1.65&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12082049">Merlini et al. (2002)</a> identified a heterozygous 83C-T transition in exon 1 of the CAV3 gene, resulting in a pro28-to-leu (P28L) substitution. Muscle biopsy showed partial CAV3 deficiency, but neither patient had any signs or symptoms of myopathy. The mutation was not found in 50 patients with different myopathies or in 100 normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12082049" 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&nbsp;CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC</strong>
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CAV3, THR64SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840799;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=rs116840799" 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=rs116840799" 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">rs121909280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909280;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=rs121909280" 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=rs121909280" 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=RCV000008785 OR RCV000024395 OR RCV001150160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008785, RCV000024395, RCV001150160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008785...</a>
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<p>The numbering of this CAV3 mutation (T64S) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Early reports designated this mutation THR63SER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 Japanese brothers with hypertrophic cardiomyopathy (CMH1; <a href="/entry/192600">192600</a>) whose father had hypertrophic cardiomyopathy and had died suddenly at the age of 41 years, <a href="#18" class="mim-tip-reference" title="Hayashi, T., Arimura, T., Ueda, K., Shibata, H., Hohda, S., Takahashi, M., Hori, H., Koga, Y., Oka, N., Imaizumi, T., Yasunami, M., Kimura, A. &lt;strong&gt;Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 313: 178-184, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14672715/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14672715&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bbrc.2003.11.101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14672715">Hayashi et al. (2004)</a> identified a thr63-to-ser (T63S) mutation in the CAV3 gene. The threonine at codon 63 is evolutionarily conserved in the scaffolding domain of caveolin-3. Two mutations involving codon 63 had earlier been reported, T63P and deletion of 3 amino acids at positions 63-65 (<a href="#0002">601253.0002</a>), in patients diagnosed with LGMD1C. <a href="#18" class="mim-tip-reference" title="Hayashi, T., Arimura, T., Ueda, K., Shibata, H., Hohda, S., Takahashi, M., Hori, H., Koga, Y., Oka, N., Imaizumi, T., Yasunami, M., Kimura, A. &lt;strong&gt;Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 313: 178-184, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14672715/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14672715&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bbrc.2003.11.101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14672715">Hayashi et al. (2004)</a> stated that the clinical findings of the index patient with the T63S mutation was mild. At the age of 16, he showed marginal concentric left ventricular hypertrophy and his left ventricular end-diastolic pressure was high in catheterization studies. His electrocardiogram showed high voltage. After 9 years' follow-up, left ventricular wall thickness was not changed markedly, but dilatation of the left ventricular and systolic dimension were increased. Similar phenotypes were found in his brother. Both of them as well as their father had no symptoms of skeletal muscle disorder and no elevation of serum creatine kinase, suggesting that they were not affected with LGMD, rippling muscle disease, or hyperCKemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14672715" 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>.0014&nbsp;MYOPATHY, DISTAL, TATEYAMA TYPE</strong>
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CAV3, ASN33LYS
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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">&#x25cf;</span> rs1008642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1008642;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/rs1008642?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1008642" 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=rs1008642" 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=RCV000008786 OR RCV001212042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008786, RCV001212042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008786...</a>
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<p>In a mother and daughter with distal myopathy and absence of caveolin-3 protein (MPDT; <a href="/entry/614321">614321</a>) on skeletal muscle biopsy, <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a> identified a heterozygous 99C-G transversion in exon 1 of the CAV3 gene, resulting in an asn33-to-lys (N33K) substitution in the N-terminal domain of the protein. Ages at onset were 30 and 27 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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&nbsp;RIPPLING MUSCLE DISEASE 2</strong>
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CAV3, GLU47LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840793 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840793;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=rs116840793" 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=rs116840793" 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=RCV000008787 OR RCV000024416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008787, RCV000024416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008787...</a>
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<p>The numbering of this CAV3 mutation (E47K) is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. Other reports designated this mutation GLU46LYS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 father and son with rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>), <a href="#23" class="mim-tip-reference" title="Madrid, R. E., Kubisch, C., Hays, A. P. &lt;strong&gt;Early-onset toe walking in rippling muscle disease due to a new caveolin-3 gene mutation.&lt;/strong&gt; Neurology 65: 1301-1303, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16247063/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16247063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000180963.85963.73&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16247063">Madrid et al. (2005)</a> identified a heterozygous 136G-A transition in exon 2 of the CAV3 gene, resulting in a glu46-to-lys (E46K) substitution. Muscle biopsy from the father showed absence of caveolin-3 immunostaining. Unusual features in both these patients included congenital pes equinus deformity and early toe walking, which resolved after orthopedic surgical correction. In addition, the father had nonprogressive mild proximal muscle weakness, and the son demonstrated percussion-induced rapid contractions of the thenar muscles without overt rippling of other muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16247063" 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="0016" class="mim-anchor"></a>
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<strong>.0016&nbsp;LONG QT SYNDROME 9</strong>
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CAV3, SER141ARG
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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">&#x25cf;</span> rs104893713 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893713;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/rs104893713?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893713" 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=rs104893713" 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=RCV000008788 OR RCV000024432" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008788, RCV000024432" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008788...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 16-year-old white male with nonexertional dyspnea and a QTc of 480 ms (LQT9; <a href="/entry/611818">611818</a>) who was negative for mutations in known LQT genes, <a href="#40" class="mim-tip-reference" title="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. &lt;strong&gt;Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.&lt;/strong&gt; Circulation 114: 2104-2112, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17060380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17060380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCULATIONAHA.106.635268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17060380">Vatta et al. (2006)</a> identified heterozygosity for a de novo 423C-G transversion in the CAV3 gene, resulting in a ser141-to-arg (S141R) substitution at a conserved residue in the functional C-terminal domain. Consistent with his negative family history and normal screening ECGs among first-degree relatives, genetic testing confirmed that neither parent carried the mutation, which was also not found in more than 1,000 control alleles. Functional studies demonstrated that S141R-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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="0017" class="mim-anchor"></a>
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<strong>.0017&nbsp;LONG QT SYNDROME 9, ACQUIRED, SUSCEPTIBILITY TO</strong>
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CAV3, PHE97CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893714;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=rs104893714" 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=rs104893714" 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=RCV000008789 OR RCV000024431" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008789, RCV000024431" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008789...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 13-year-old asthmatic girl with long QT syndrome (LQT9; <a href="/entry/611818">611818</a>) who was negative for mutations in known LQT genes, <a href="#40" class="mim-tip-reference" title="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. &lt;strong&gt;Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.&lt;/strong&gt; Circulation 114: 2104-2112, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17060380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17060380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCULATIONAHA.106.635268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17060380">Vatta et al. (2006)</a> identified heterozygosity for a de novo 290T-G transversion in the CAV3 gene, resulting in a phe97-to-cys (F97C) substitution at a highly conserved residue in the transmembrane domain. The patient presented with shortness of breath and chest pain; ECG showed marked QT prolongation with a QTc of 532 ms, which was present only, but reproducibly, on beta-agonist inhaler therapy for her asthma. The family history was unremarkable, and screening ECGs in all first-degree relatives showed normal QTc. The mutation was not found in either of her parents or in more than 1,000 control alleles. Functional studies demonstrated that F97C-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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="0018" class="mim-anchor"></a>
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<strong>.0018&nbsp;LONG QT SYNDROME 9</strong>
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LONG QT SYNDROME 2/9, DIGENIC, INCLUDED
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CAV3, THR78MET
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">&#x25cf;</span> rs72546668 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72546668;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/rs72546668?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs72546668" 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=rs72546668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008790 OR RCV000008791 OR RCV000024406 OR RCV000039801 OR RCV000168328 OR RCV000242756 OR RCV000769173 OR RCV000987088 OR RCV001144019 OR RCV003924817 OR RCV004764897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008790, RCV000008791, RCV000024406, RCV000039801, RCV000168328, RCV000242756, RCV000769173, RCV000987088, RCV001144019, RCV003924817, RCV004764897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008790...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated individuals with long QT syndrome (LQT9; <a href="/entry/611818">611818</a>), <a href="#40" class="mim-tip-reference" title="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. &lt;strong&gt;Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.&lt;/strong&gt; Circulation 114: 2104-2112, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17060380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17060380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCULATIONAHA.106.635268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17060380">Vatta et al. (2006)</a> identified heterozygosity for a 233C-T transition in the CAV3 gene, resulting in a thr78-to-met (T78M) substitution at a highly conserved residue. All 3 patients had a positive family history, but family members declined further genotyping. One patient had biallelic digenic mutations: she was a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, and was found to carry a A913V mutation in the LQT2-associated KCNH2 gene (<a href="/entry/152427#0024">152427.0024</a>) as well as the T78M mutation. The other 2 patients, who were negative for mutations in other known LQTS genes, were an 8-year-old boy with nonexertional syncope and marked sinus bradycardia with a QTc of 433 ms and an asymptomatic 40-year-old male who had a QTc of 456 ms. The T78M mutation was not found in more than 1,000 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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 frozen necropsy tissue from a 2-month-old black female infant who died of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>), <a href="#5" class="mim-tip-reference" title="Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. &lt;strong&gt;Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.&lt;/strong&gt; Heart Rhythm 4: 161-166, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17275750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17275750&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17275750[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.hrthm.2006.11.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17275750">Cronk et al. (2007)</a> identified the T78M mutation in the CAV3 gene. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275750" 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="0019" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0019&nbsp;LONG QT SYNDROME 9</strong>
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CAV3, ALA85THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893715;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=rs104893715" 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=rs104893715" 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=RCV000008792 OR RCV000024430" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008792, RCV000024430" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008792...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 36-year-old female who suffered a cardiac arrest while sleeping (LQT9; <a href="/entry/611818">611818</a>), <a href="#40" class="mim-tip-reference" title="Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. &lt;strong&gt;Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.&lt;/strong&gt; Circulation 114: 2104-2112, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17060380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17060380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/CIRCULATIONAHA.106.635268&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17060380">Vatta et al. (2006)</a> identified heterozygosity for a 253G-A transition in the CAV3 gene, resulting in an ala85-to-thr (A85T) substitution at a conserved residue. The mutation was not found in more than 1,000 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" 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>.0020&nbsp;LONG QT SYNDROME 9</strong>
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CAV3, VAL14LEU
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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">&#x25cf;</span> rs121909281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909281;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/rs121909281?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909281" 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=rs121909281" 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=RCV000008793 OR RCV000024433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008793, RCV000024433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008793...</a>
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<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 frozen necropsy tissue from a 6-month-old black male infant who died of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>), <a href="#5" class="mim-tip-reference" title="Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. &lt;strong&gt;Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.&lt;/strong&gt; Heart Rhythm 4: 161-166, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17275750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17275750&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17275750[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.hrthm.2006.11.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17275750">Cronk et al. (2007)</a> identified a 40G-C transversion in the CAV3 gene, resulting in a val14-to-leu (V14L) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275750" 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&nbsp;LONG QT SYNDROME 9</strong>
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CAV3, LEU79ARG
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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">&#x25cf;</span> rs121909282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909282;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/rs121909282?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">&#x25cf;</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909282" 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=rs121909282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008794 OR RCV000024434 OR RCV001246513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008794, RCV000024434, RCV001246513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008794...</a>
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<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by <a href="#10" class="mim-tip-reference" title="Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. &lt;strong&gt;Molecular and muscle pathology in a series of caveolinopathy patients.&lt;/strong&gt; Hum. Mutat. 25: 82-89, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580566/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15580566&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20119&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15580566">Fulizio et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580566" 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 frozen necropsy tissue from an 8-month-old black female infant who died of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>), <a href="#5" class="mim-tip-reference" title="Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. &lt;strong&gt;Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.&lt;/strong&gt; Heart Rhythm 4: 161-166, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17275750/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17275750&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17275750[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.hrthm.2006.11.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17275750">Cronk et al. (2007)</a> identified a 236T-G transversion in the CAV3 gene, resulting in a leu79-to-arg (L79R) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275750" 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>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
<a id="Aravamudan2003" class="mim-anchor"></a>
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Aravamudan, B., Volonte, D., Ramani, R., Gursoy, E., Lisanti, M. P., London, B., Galbiati, F.
<strong>Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype.</strong>
Hum. Molec. Genet. 12: 2777-2788, 2003. Note: Erratum: Hum. Molec. Genet. 13: 149 only, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddg313" target="_blank">Full Text</a>]
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<a id="Betz2001" class="mim-anchor"></a>
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Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C.
<strong>Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.</strong>
Nature Genet. 28: 218-219, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431690</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/90050" target="_blank">Full Text</a>]
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<a id="Cagliani2003" class="mim-anchor"></a>
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Cagliani, R., Bresolin, N., Prelle, A., Gallanti, A., Fortunato, F., Sironi, M., Ciscato, P., Fagiolari, G., Bonato, S., Galbiati, S., Corti, S., Lamperti, C., Moggio, M., Comi, G. P.
<strong>A CAV3 microdeletion differentially affects skeletal muscle and myocardium.</strong>
Neurology 61: 1513-1519, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14663034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14663034</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14663034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000097320.35982.03" target="_blank">Full Text</a>]
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<a id="Carbone2000" class="mim-anchor"></a>
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Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C.
<strong>Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia.</strong>
Neurology 54: 1373-1376, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10746614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10746614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.54.6.1373" target="_blank">Full Text</a>]
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<a id="Cronk2007" class="mim-anchor"></a>
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Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J.
<strong>Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.</strong>
Heart Rhythm 4: 161-166, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17275750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17275750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17275750[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=17275750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.hrthm.2006.11.030" target="_blank">Full Text</a>]
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<a id="de Paula2001" class="mim-anchor"></a>
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de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M.
<strong>Mutations in the caveolin-3 gene: when are they pathogenic?</strong>
Am. J. Med. Genet. 99: 303-307, 2001.
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[<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999&lt;::aid-ajmg1168&gt;3.0.co;2-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.33.10.842" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000076486.57572.5c" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.10442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20119" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.160249097" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.274.36.25632" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.272.41.25437" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.jns.2008.09.009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.20.3047" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2003.11.101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018926" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20350" target="_blank">Full Text</a>]
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Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M.
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[<a href="https://doi.org/10.1002/ana.10501" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr201" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000180963.85963.73" target="_blank">Full Text</a>]
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Matsuda, C., Hayashi, Y. K., Ogawa, M., Aoki, M., Murayama, K., Nishino, I., Nonaka, I., Arahata, K., Brown, R. H., Jr.
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[<a href="https://doi.org/10.1093/hmg/10.17.1761" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.5.871" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.73.1.65" target="_blank">Full Text</a>]
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Nature Genet. 18: 365-368, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9537420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9537420</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9537420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0498-365" target="_blank">Full Text</a>]
</p>
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<a id="29" class="mim-anchor"></a>
<a id="Nixon2005" class="mim-anchor"></a>
<div class="">
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Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G.
<strong>Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning.</strong>
Hum. Molec. Genet. 14: 1727-1743, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddi179" target="_blank">Full Text</a>]
</p>
</div>
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<a id="30" class="mim-anchor"></a>
<a id="Ohsawa2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y.
<strong>Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.</strong>
J. Clin. Invest. 116: 2924-2934, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[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=17039257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI28520" target="_blank">Full Text</a>]
</p>
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<a id="31" class="mim-anchor"></a>
<a id="Ohsawa2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ohsawa, Y., Toko, H., Katsura, M., Morimoto, K., Yamada, H., Ichikawa, Y., Murakami, T., Ohkuma, S., Komuro, I., Sunada, Y.
<strong>Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.</strong>
Hum. Molec. Genet. 13: 151-157, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddh014" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
<a id="Oshikawa2004" class="mim-anchor"></a>
<div class="">
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Oshikawa, J., Otsu, K., Toya, Y., Tsunematsu, T., Hankins, R., Kawabe, J., Minamisawa, S., Umemura, S., Hagiwara, Y., Ishikawa, Y.
<strong>Insulin resistance in skeletal muscles of caveolin-3-null mice.</strong>
Proc. Nat. Acad. Sci. 101: 12670-12675, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15314230[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=15314230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0402053101" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
<a id="Ricker1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ricker, K., Moxley, R. T., Rohkamm, R.
<strong>Rippling muscle disease.</strong>
Arch. Neurol. 46: 405-408, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2705900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2705900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2705900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1989.00520400065020" target="_blank">Full Text</a>]
</p>
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<a id="34" class="mim-anchor"></a>
<a id="Sotgia1999" class="mim-anchor"></a>
<div class="">
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Sotgia, F., Minetti, C., Lisanti, M. P.
<strong>Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.</strong>
FEBS Lett. 452: 177-180, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10386585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10386585</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10386585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0014-5793(99)00658-4" target="_blank">Full Text</a>]
</p>
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<a id="Straub2018" class="mim-anchor"></a>
<div class="">
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Straub, V., Murphy, A., Udd, B.
<strong>229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.</strong>
Neuromusc. Disord. 28: 702-710, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30055862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30055862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30055862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.nmd.2018.05.007" target="_blank">Full Text</a>]
</p>
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<a id="36" class="mim-anchor"></a>
<a id="Sunada2001" class="mim-anchor"></a>
<div class="">
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Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T.
<strong>Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity.</strong>
Hum. Molec. Genet. 10: 173-178, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159934</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.3.173" target="_blank">Full Text</a>]
</p>
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<a id="37" class="mim-anchor"></a>
<a id="Tang1996" class="mim-anchor"></a>
<div class="">
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Tang, Z., Scherer, P. E., Okamoto, T., Song, K., Chu, C., Kohtz, D. S., Nishimoto, I., Lodish, H. F., Lisanti, M. P.
<strong>Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.</strong>
J. Biol. Chem. 271: 2255-2261, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8567687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8567687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8567687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1074/jbc.271.4.2255" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
<a id="Tateyama2002" class="mim-anchor"></a>
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Tateyama, M., Aoki, M., Nishino, I., Hayashi, Y. K., Sekiguchi, S., Shiga, Y., Takahashi, T., Onodera, Y., Haginoya, K., Kobayashi, K., Iinuma, K., Nonaka, I., Arahata, K., Itoyama, Y.
<strong>Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.</strong>
Neurology 58: 323-325, 2002. Note: Erratum: Neurology 58: 839 only, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11805270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11805270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11805270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.58.2.323" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
<a id="Torbergsen1975" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Torbergsen, T.
<strong>A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita Thomsen.</strong>
Acta Neurol. Scand. 51: 225-232, 1975.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1146501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1146501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1146501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1600-0404.1975.tb07603.x" target="_blank">Full Text</a>]
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<a id="Vatta2006" class="mim-anchor"></a>
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Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A.
<strong>Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.</strong>
Circulation 114: 2104-2112, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17060380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17060380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.635268" target="_blank">Full Text</a>]
</p>
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<a id="Vorgerd1999" class="mim-anchor"></a>
<div class="">
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Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W.
<strong>Phenotypic variability in rippling muscle disease.</strong>
Neurology 52: 1453-1459, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227634</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10227634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.52.7.1453" target="_blank">Full Text</a>]
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<a id="Vorgerd2001" class="mim-anchor"></a>
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Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W.
<strong>A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.</strong>
Neurology 57: 2273-2277, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11756609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11756609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11756609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.57.12.2273" target="_blank">Full Text</a>]
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Patricia A. Hartz - updated : 4/10/2013
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Cassandra L. Kniffin - updated : 11/1/2011<br>George E. Tiller - updated : 10/28/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Cassandra L. Kniffin - updated : 12/7/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 1/31/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 4/27/2005<br>Cassandra L. Kniffin - updated : 2/17/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 10/6/2004<br>Cassandra L. Kniffin - updated : 8/30/2004<br>Cassandra L. Kniffin - updated : 2/3/2004<br>Cassandra L. Kniffin - updated : 1/20/2004<br>Cassandra L. Kniffin - updated : 6/6/2003<br>Cassandra L. Kniffin - reorganized : 5/22/2003<br>Cassandra L. Kniffin - updated : 5/8/2003<br>Cassandra L. Kniffin - updated : 12/30/2002<br>George E. Tiller - updated : 1/23/2002<br>Ada Hamosh - updated : 6/27/2001<br>George E. Tiller - updated : 4/13/2001<br>George E. Tiller - updated : 3/5/2001<br>George E. Tiller - updated : 12/14/2000<br>Victor A. McKusick - updated : 9/26/2000<br>Victor A. McKusick - updated : 10/26/1999<br>Victor A. McKusick - updated : 3/12/1999<br>Victor A. McKusick - updated : 5/22/1998<br>Victor A. McKusick - updated : 3/31/1998
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Mark H. Paalman : 5/9/1996
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carol : 11/01/2022<br>carol : 07/24/2019<br>carol : 09/27/2018<br>carol : 09/26/2018<br>carol : 09/25/2018<br>carol : 04/25/2018<br>carol : 04/18/2018<br>carol : 03/27/2017<br>carol : 09/16/2016<br>mgross : 04/10/2013<br>mgross : 4/10/2013<br>carol : 3/21/2013<br>mgross : 3/13/2013<br>terry : 10/4/2012<br>terry : 11/1/2011<br>carol : 11/1/2011<br>ckniffin : 11/1/2011<br>carol : 1/13/2011<br>alopez : 2/9/2009<br>wwang : 10/28/2008<br>carol : 7/9/2008<br>carol : 7/9/2008<br>carol : 3/10/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>wwang : 7/20/2007<br>wwang : 2/9/2007<br>ckniffin : 2/5/2007<br>wwang : 12/11/2006<br>ckniffin : 12/7/2006<br>wwang : 3/9/2006<br>terry : 2/17/2006<br>wwang : 2/6/2006<br>terry : 1/31/2006<br>wwang : 12/9/2005<br>terry : 12/7/2005<br>terry : 8/3/2005<br>wwang : 5/10/2005<br>ckniffin : 4/27/2005<br>wwang : 2/21/2005<br>ckniffin : 2/17/2005<br>ckniffin : 2/17/2005<br>wwang : 2/16/2005<br>wwang : 2/11/2005<br>terry : 2/4/2005<br>alopez : 10/7/2004<br>terry : 10/6/2004<br>carol : 9/7/2004<br>ckniffin : 8/30/2004<br>tkritzer : 2/9/2004<br>ckniffin : 2/3/2004<br>tkritzer : 1/23/2004<br>ckniffin : 1/20/2004<br>carol : 6/6/2003<br>ckniffin : 6/2/2003<br>carol : 5/22/2003<br>ckniffin : 5/20/2003<br>ckniffin : 5/20/2003<br>ckniffin : 5/16/2003<br>carol : 5/16/2003<br>ckniffin : 5/8/2003<br>cwells : 1/7/2003<br>ckniffin : 12/30/2002<br>terry : 3/28/2002<br>cwells : 2/13/2002<br>cwells : 1/23/2002<br>carol : 6/29/2001<br>carol : 6/29/2001<br>mgross : 6/29/2001<br>mgross : 6/28/2001<br>mgross : 6/28/2001<br>terry : 6/27/2001<br>cwells : 5/4/2001<br>cwells : 4/25/2001<br>cwells : 4/13/2001<br>cwells : 3/6/2001<br>cwells : 3/5/2001<br>cwells : 3/2/2001<br>cwells : 1/16/2001<br>terry : 12/14/2000<br>mcapotos : 10/6/2000<br>mcapotos : 10/3/2000<br>terry : 9/26/2000<br>terry : 2/28/2000<br>carol : 11/3/1999<br>terry : 10/26/1999<br>terry : 5/20/1999<br>carol : 3/15/1999<br>terry : 3/12/1999<br>carol : 2/10/1999<br>terry : 6/3/1998<br>terry : 5/22/1998<br>joanna : 5/15/1998<br>alopez : 4/8/1998<br>alopez : 4/1/1998<br>terry : 3/31/1998<br>carol : 3/21/1998<br>jamie : 5/29/1997<br>mark : 5/13/1996<br>mark : 5/10/1996<br>mark : 5/9/1996<br>mark : 5/9/1996
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<strong>*</strong> 601253
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CAVEOLIN 3; CAV3
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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</p>
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<h4>
<span class="mim-font">
M-CAVEOLIN
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<span class="mim-text-font">
<strong><em>HGNC Approved Gene Symbol: CAV3</em></strong>
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<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 711265009, 83978005; &nbsp;
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<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: 3p25.3
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : 3:8,733,802-8,746,758 </span>
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</strong>
<span class="small">(from NCBI)</span>
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<h4>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
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<th>
Inheritance
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Phenotype <br /> mapping key
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<td rowspan="5">
<span class="mim-font">
3p25.3
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<td>
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Cardiomyopathy, familial hypertrophic
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<span class="mim-font">
192600
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<td>
<span class="mim-font">
Autosomal dominant; Digenic dominant
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3
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<td>
<span class="mim-font">
Creatine phosphokinase, elevated serum
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<span class="mim-font">
123320
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<td>
<span class="mim-font">
Autosomal dominant
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<span class="mim-font">
3
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<td>
<span class="mim-font">
Long QT syndrome 9
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<span class="mim-font">
611818
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<td>
<span class="mim-font">
Autosomal dominant
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<span class="mim-font">
3
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<td>
<span class="mim-font">
Myopathy, distal, Tateyama type
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<span class="mim-font">
614321
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<td>
<span class="mim-font">
Autosomal dominant
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</td>
<td>
<span class="mim-font">
3
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<td>
<span class="mim-font">
Rippling muscle disease 2
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<td>
<span class="mim-font">
606072
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<td>
<span class="mim-font">
Autosomal dominant
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<td>
<span class="mim-font">
3
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</td>
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</tbody>
</table>
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<h4>
<span class="mim-font">
<strong>TEXT</strong>
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<span class="mim-font">
<strong>Description</strong>
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<p>Caveolin-3 (M-caveolin) is the muscle-specific form of the caveolin protein family, which also includes caveolin-1 (CAV1; 601047) and caveolin-2 (CAV2; 601048). Caveolins are the principal protein components of caveolae ('little caves'), 50 to 100 nm invaginations found in most cell types which represent appendages or subcompartments of plasma membranes (Minetti et al., 1998). </p><p>Caveolin-3 plays a role in muscle development and physiology. In adult muscle, it is present throughout the T tubule system, but is clustered in subsarcolemmal areas critical for the electrical transmission of the contractile impulse. In the sarcolemma, caveolin-3 belongs to the dystrophin-glycoprotein complex and confers stability to the muscle cell membrane. In addition to these structural roles, caveolin-3 has functional roles in signaling pathways and energy metabolism (review by Gazzerro et al., 2010). </p>
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<h4>
<span class="mim-font">
<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
<p>To identify other putative members of the G protein-associated caveolin gene family, Tang et al. (1996) searched existing databases for genomic sequences related to the protein sequence of caveolin-1. They identified a rat sequence that appeared to encode a novel caveolin-like gene and designed oligonucleotide primers with which to amplify purified rat genomic DNA. They designated the new gene caveolin-3 (CAV3). Rat caveolin-3 is approximately 65% identical and 85% similar to rat caveolin-1. The authors noted that a single stretch of amino acids (FEDVIAEP) is identical in caveolin-1, -2, and -3, and may represent a 'caveolin signature sequence' characteristic of this family. Tang et al. (1996) further characterized the biochemistry, cellular localization, and tissue specificity of caveolin-3. They detected the CAV3 transcript only in rat skeletal muscle, diaphragm, and heart tissues, but noted that CAV3 expression was specific to the endothelial cells surrounding the muscle fibers. Additionally, they observed that a caveolin-3-derived polypeptide conserved in caveolin-1 either suppresses or stimulates the basal GTPase activity of purified heterotrimeric G proteins (see 600239) in a concentration-dependent manner. </p><p>McNally et al. (1998) cloned the CAV3 gene and found that the cDNA encodes an open reading frame of 150 amino acids with 96% homology to the rat and mouse sequences. CAV3 mRNA was expressed exclusively in cardiac and skeletal muscle. </p><p>Minetti et al. (1998) stated that caveolin-3 contains a 20-amino acid scaffolding domain (residues 54 to 73) that is critical for homo-oligomerization and for interaction with several caveolin-associated signaling molecules. A 33-amino acid hydrophobic domain (residues 74 to 106) of caveolin-3, which spans the membrane, is thought to form a hairpin loop within the cell membrane, allowing both the amino- and carboxy-terminal domains to face the cytoplasm. Comparison of caveolins-1, -2, and -3 with caveolins-1 and -2 of Caenorhabditis elegans showed that only 12 amino acid residues are invariant between worms and man. Nixon et al. (2005) noted that CAV3 shares 72% identity with its zebrafish homolog. </p>
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<h4>
<span class="mim-font">
<strong>Gene Structure</strong>
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<span class="mim-text-font">
<p>McNally et al. (1998) determined that the CAV3 gene contains 2 exons. </p>
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<h4>
<span class="mim-font">
<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
<p>By fluorescence in situ hybridization, Minetti et al. (1998) and McNally et al. (1998) mapped the CAV3 gene to chromosome 3p25. </p><p>To map the CAV3 gene more precisely, Sotgia et al. (1999) isolated 3 independent BAC clones containing the human CAV3 gene. Using a PCR-based approach, they determined that these clones contained both exons 1 and 2 of the CAV3 gene. In addition, they performed microsatellite marker analysis of these BAC clones, using a panel of 13 markers that are known to map within the 3p25 region. They identified 3 markers within these BAC clones, one of which, D3S18, is a marker for 2 known human diseases, von Hippel-Lindau disease (VHL; 193300) and 3p- syndrome. Two of the markers were known to map in the vicinity of the 3-prime end of the oxytocin receptor gene (OXTR; 167055). Sotgia et al. (1999) showed that these BACs contained all 4 exons of the oxytocin receptor gene, and that the genes encoding CAV3 and OXTR are located approximately 7 to 10 kb apart and are transcribed in opposite orientation. </p>
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<h4>
<span class="mim-font">
<strong>Gene Function</strong>
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</h4>
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<span class="mim-text-font">
<p>McNally et al. (1998) showed that caveolin-3 copurifies with dystrophin (300377) in rat skeletal muscle membrane, suggesting a role in muscular dystrophy. The authors noted, however, that a significant fraction of the caveolin present in the rat skeletal muscle did not copurify with dystrophin, suggesting that caveolin is not associated exclusively with the dystrophin-glycoprotein complex (DGC) in muscle. </p><p>Dysferlin (DYSF; 603009) is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited forms of muscular dystrophy designated Miyoshi myopathy (MM; 254130) and limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), respectively. Matsuda et al. (2001) reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae. Abnormal localization of dysferlin was seen in muscles from patients diagnosed with limb-girdle muscular dystrophy type 1C (LGMD1C), reclassified as rippling muscle disease (RMD2; 606072) by Straub et al. (2018), including one with a novel missense mutation in CAV3. </p><p>The 3p- syndrome results from a hemizygous deletion of 3pter-p25 and is characterized by growth retardation, specific craniofacial features (microcephaly, ptosis, micrognathia), mental retardation, and cardiac septal defects (Drumheller et al., 1996). Sotgia et al. (1999) suggested that the CAV3 gene may be deleted in 3p- syndrome. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
<p><strong><em>Skeletal Muscle Phenotypes</em></strong></p><p>
Mutations in the CAV3 gene can cause different skeletal muscle phenotypes, including rippling muscle disease-2 (RMD2; 606072); isolated hyperCKemia (123320); and distal myopathy (MPDT; 614321). A form of limb-girdle muscular dystrophy (LGMD1C) caused by mutation in the CAV3 gene was reclassified by Straub et al. (2018) as RMD2. Many patients show an overlap of these skeletal muscle entities, and some authors have suggested that the caveolinopathies constitute a clinical continuum. Moreover, there are no genotype/phenotype correlations, the same mutation can cause heterogeneous phenotypes, and there is intrafamilial variability. Most of the mutations cause a loss of caveolin-3 in skeletal muscle biopsy (review by Gazzerro et al., 2010). </p><p>In 2 families diagnosed with LGMD1C, Minetti et al. (1998) identified heterozygous mutations in the CAV3 gene: a missense mutation in the membrane-spanning region (P105L; 601253.0001) and a microdeletion in the scaffolding domain (601253.0002). The mutations altered conserved invariant amino acid residues. Minetti et al. (1998) predicted that these mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane. </p><p>Among 82 patients with muscular dystrophy of unknown genetic etiology, McNally et al. (1998) identified 1 female with a homozygous missense change in the CAV3 gene (G56S; 601253.0003). A second patient was identified with a heterozygous change on 1 allele (C72W; 601253.0004). Both mutations fall within a cytoplasmic region of caveolin-3 that had been implicated directly in inhibiting activity of neuronal nitric oxide synthase (NOS1; 163731). NOS1 is part of the dystrophin-glycoprotein complex, and its association with the muscle membrane is altered in Duchenne muscular dystrophy (DMD; 310200). Among 100 Brazilian normal control subjects without LGMD, de Paula et al. (2001) found 4 subjects who were heterozygous for the G55S change and 1 subject who was heterozygous for the C72W change. The authors concluded that the G56S and C72W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. </p><p>Herrmann et al. (2000) reported a 4-year-old girl presenting with myalgia and muscle cramps due to a heterozygous substitution in the caveolin-3 gene (A46T; 601253.0005) that prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan (DAG1; 128239) expression was detected in the caveolin-3-deficient patient. The authors hypothesized common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies and caveolin-3-deficient limb-girdle muscular dystrophy. </p><p>Carbone et al. (2000) identified a de novo recurrent sporadic mutation in the CAV3 gene (R27Q; 601253.0007) in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; 123320) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Carbone et al. (2000) concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. </p><p>In 5 families with autosomal dominant rippling muscle disease, Betz et al. (2001) identified 4 missense mutations in the CAV3 gene (see, e.g., 601253.0001). They found that the same mutations in the CAV3 gene can give rise to rippling muscle disease and sporadic hyperCKemia. </p><p>Fulizio et al. (2005) screened 663 patients with various phenotypes of unknown etiology (primarily clinical diagnoses of unclassified limb-girdle muscular dystrophy, hyperCKemia, and proximal myopathy), for caveolin-3 protein deficiency, and identified 8 caveolin-deficient patients from 7 families with CAV3 mutations. Four of the patients had the A46T mutation (601253.0005). The authors noted the wide phenotypic and histologic variations in patients with the same mutation or from the same families, precluding a clear genotype/phenotype correlation. Fulizio et al. (2005) estimated that caveolinopathies represent 1% of both unclassified LGMD and other phenotypes, and demonstrated that caveolin-3 protein deficiencies are a highly sensitive and specific marker of primary caveolinopathy. </p><p><strong><em>Hypertrophic Cardiomyopathy and Long QT Syndrome</em></strong></p><p>
Hayashi et al. (2004) examined the CAV3 gene for mutation in patients with hypertrophic cardiomyopathy (CMH; 192600) or dilated cardiomyopathy. They found a thr64-to-ser mutation (601253.0013) in 2 brothers with hypertrophic cardiomyopathy but not in their mother, who did not show left ventricular hypertrophy. Thus, it was suggested that the mutation had been inherited from their father, but this could not be confirmed since the father, who was also affected with hypertrophic cardiomyopathy, had died suddenly at the age of 41 years. </p><p>Vatta et al. (2006) analyzed the CAV3 gene in 905 unrelated patients with long QT syndrome who had previously been tested for mutations in known LQT genes and identified 4 heterozygous missense mutations in 6 patients (601253.0016-601253.0019, respectively) with LQT9 (611818). The mutations were not found in more than 1,000 control alleles. Electrophysiologic analysis of transiently transfected HEK293 cells stably expressing the cardiac sodium channel demonstrated that the mutant caveolin-3 resulted in a 2- to 3-fold increase in the late sodium current compared with wildtype caveolin-3. One patient had biallelic digenic mutations, with a missense mutation in the LQT2 (613688)-associated KCNH2 gene (152427) as well as in the CAV3 gene (see 601253.0018 and 152427.0024) </p><p><strong><em>Sudden Infant Death Syndrome</em></strong></p><p>
Cronk et al. (2007) analyzed the CAV3 gene in necropsy tissue from 134 unrelated cases of sudden infant death syndrome (SIDS; 272120) and identified 3 missense mutations in 3 of 50 black infants (601253.0018; 601253.0020; and 601253.0021). No mutations were detected in 1 Hispanic or 83 white infants. Voltage-clamp studies demonstrated a gain-of-function phenotype for all 3 CAV3 mutations, with a 5-fold increase in late sodium current compared to controls. </p>
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<h4>
<span class="mim-font">
<strong>Animal Model</strong>
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<span class="mim-text-font">
<p>Hagiwara et al. (2000) developed caveolin-3-deficient mice for use as animal models of caveolinopathy. Caveolin-3 mRNA and its protein were absent in homozygous mutant mice. Muscle degeneration was recognized in soleus muscle at 8 weeks of age and in the diaphragm from 8 to 30 weeks, although there was no difference in growth and movement between wildtype and mutant mice. No apparent muscle degeneration was observed in heterozygous mutant mice, consistent with autosomal recessive transmission of the phenotype. This is in contrast to the dominant-negative acting missense mutations found in human LGMD1C. Note that LGMD1C has been reclassified as RMD2. </p><p>Duchenne muscular dystrophy patients and mdx mice show elevated levels of caveolin-3 expression in skeletal muscle. To investigate whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of the disorder, Galbiati et al. (2000) overexpressed wildtype caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3-overexpressing transgenic mice showed a dramatic increase in the number of sarcolemmal muscle cell caveolae; a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and downregulation of dystrophin and beta-dystroglycan protein expression. In addition, the mice showed elevated serum creatine kinase levels, consistent with the myonecrosis observed morphologically. </p><p>Sunada et al. (2001) generated transgenic mice expressing the pro105-to-leu mutant caveolin-3 (P105L; 601253.0001). Mice showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, suggesting a dominant-negative effect of mutant caveolin-3. Caveolin-3 had been shown to interact with neuronal nitric oxide synthase (nNOS; 163731) and inhibit its catalytic activity (Garcia-Cardena et al., 1997). Sunada et al. (2001) found a great increase of nNOS activity in the transgenic skeletal muscle, suggesting a role for nitric oxide synthase in muscle fiber degeneration in caveolin-3 deficiency. </p><p>Aravamudan et al. (2003) showed that Cav3-overexpressing transgenic mice had severe cardiac tissue degeneration, fibrosis, and a reduction in cardiac functions. Dystrophin and its associated glycoproteins were downregulated in Cav3 transgenic hearts. In addition, the activity of nitric oxide synthase was downregulated by high levels of caveolin-3 in the heart. </p><p>Caveolin-3 binds to eNOS (NOS3; 163729) in cardiac myocytes and nNOS in skeletal myocytes. Ohsawa et al. (2004) characterized the biochemical and cardiac parameters of P105L mutant mice, a model of LGMD1C (RMD2). Transgenic mouse hearts demonstrated hypertrophic cardiomyopathy, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of Cav3 protein. Cardiac muscle showed activation of eNOS catalytic activity without increased expression of all NOS isoforms. Ohsawa et al. (2004) suggested that a moderate increase in eNOS activity associated with loss of Cav3 may result in hypertrophic cardiomyopathy. </p><p>Oshikawa et al. (2004) examined the role of Cav3 in insulin signaling in a strain of Cav3 knockout mice originally developed as a model of DMD. They found Cav3 knockout led to the development of insulin resistance, as shown by decreased glucose uptake in skeletal muscles, impaired glucose tolerance, and increased serum lipids. Impairments were augmented in the presence of streptozotocin, a pancreatic beta cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of insulin receptors (INSR; 147670) and downstream molecules, such as Irs1 (147545) and Akt (see AKT1; 164730), was attenuated in the skeletal muscle of Cav3-null mice, but not in liver, without affecting Insr expression or subcellular localization. Cav3 gene transfer restored insulin signaling in skeletal muscles. Oshikawa et al. (2004) concluded that CAV3 is an enhancer of insulin signaling in skeletal muscle but it does not act as a scaffolding molecule for INSR. </p><p>Nixon et al. (2005) showed that in zebrafish embryonic development Cav3 and caveolae were located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan (DAG1; 128239) was restricted to the muscle fiber ends. Downregulation of Cav3 expression caused gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers revealed defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3 P105L (601253.0001), caused severe disruption of muscle differentiation. Knockdown of Cav3 resulted in a dramatic upregulation of Eng1a (see EN1; 131290) expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. Nixon et al. (2005) concluded that Cav3 is essential to muscle development, particularly for correct intracellular organization and myoblast fusion. </p><p>In COS-7 cells, Ohsawa et al. (2006) found that caveolin-3 inhibited signaling of myostatin (MSTN; 601788), a molecule that negatively regulates skeletal muscle volume by direct interaction with and inhibition of the type I myostatin receptors ALK4 (601300) and ALK5 (190181). Doubly transgenic mice with both Cav3 deficiency and myostatin inhibition showed increased numbers and size of myofibers compared to singly Cav3-deficient mice, effectively reversing the muscle atrophy induced by Cav3 deficiency. In addition, intraperitoneal injection of a myostatin inhibitor improved functional muscle weakness in Cav3-deficient mice. Ohsawa et al. (2006) suggested that caveolin-3 normally suppresses myostatin signaling and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in this mouse model of LGMD1C (RMD2). </p><p>Kuga et al. (2011) found that Cav3(P104L) accumulated in the Golgi apparatus of transgenic mice and in transfected COS-7 cells. Use of wildtype and hemizygous and homozygous Cav3(P104L) mutant mice revealed a dose-dependent induction of the endoplasmic reticulum stress response by Cav3(P104L), including upregulation of the molecular chaperone Gpr78 (HSPA5; 138120) and a mild apoptotic skeletal muscle phenotype. </p>
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<h4>
<span class="mim-font">
<strong>ALLELIC VARIANTS</strong>
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<strong>21 Selected Examples):</strong>
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</h4>
<div>
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<h4>
<span class="mim-font">
<strong>.0001 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
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</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, PRO105LEU
<br />
SNP: rs116840805,
ClinVar: RCV000008765, RCV000024379, RCV005089211
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</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation PRO104LEU. </p><p>In 4 members over 2 generations of an Italian family diagnosed with limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Minetti et al. (1998) identified a heterozygous 311C-to-T transition in the CAV3 gene, resulting in a pro104-to-leu (P104L) substitution. </p><p>In family A with rippling muscle disease described by Ricker et al. (1989), Betz et al. (2001) identified the P105L mutation. </p><p><strong><em>Variant Function</em></strong></p><p>
Galbiati et al. (1999) stated that P104 resides in the membrane-spanning domain of CAV3. They found that rat Cav3 with the P104L mutation was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. </p>
</span>
</div>
<div>
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<div>
<h4>
<span class="mim-font">
<strong>.0002 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, 9-BP DEL, NT186
<br />
SNP: rs116840800, rs199476331,
ClinVar: RCV000008767, RCV000024380
</span>
</div>
<div>
<span class="mim-text-font">
<p>Minetti et al. (1998) demonstrated that 4 affected members in 3 generations of an Italian family diagnosed with autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), had a 9-bp deletion beginning at nucleotide 186 of the CAV3 gene, which resulted in the loss of 3 amino acids (residues 63-65) without changing the open reading frame. </p><p><strong><em>Variant Function</em></strong></p><p>
Galbiati et al. (1999) stated that the residues lost in this deletion (TFT) reside within the caveolin scaffolding domain. They found that rat Cav3 with the TFT deletion was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. </p>
</span>
</div>
<div>
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</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0003 &nbsp; RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, GLY56SER
<br />
SNP: rs72546667,
gnomAD: rs72546667,
ClinVar: RCV000008768, RCV000039799, RCV000119393, RCV000171805, RCV000249765, RCV000362621, RCV000987086, RCV001082614, RCV001150159, RCV001171080, RCV002496306
</span>
</div>
<div>
<span class="mim-text-font">
<p>This variant, formerly titled MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, AUTOSOMAL RECESSIVE, has been reclassified as a variant of unknown significance based on the findings by de Paula et al. (2001) and Hamosh (2018). Note that limb-girdle muscular dystrophy (LGMD1C) was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072). </p><p>The numbering of this CAV3 mutation (G56S) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation GLY55SER. </p><p>McNally et al. (1998) found homozygosity for a gly55-to-ser change (G55S) in 1 of 82 patients with muscular dystrophy screened for mutations in the CAV3 gene. This patient was the only affected member of her family, and developed proximal muscle weakness in the first decade. The mutation was not identified in 200 control chromosomes. Expression of dystrophin, the sarcoglycans, and caveolin-3 was grossly normal in a skeletal muscle biopsy from the patient, and the authors suggested that the G55S change may not alter the intracellular location of the protein, yet may interfere with the normal function of the protein in the membrane. </p><p>Among 61 Brazilian patients diagnosed with LGMD, de Paula et al. (2001) identified 2 patients with a heterozygous G55S mutation. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening of 200 normal Brazilian chromosomes revealed heterozygosity for the G55S change in 4 subjects and for a C71W change (601253.0004) in 1 subject. The authors concluded that the G55S and C71W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. The abnormal phenotype in the 2 patients is likely caused by mutation in another LGMD gene. </p><p>Hamosh (2018) found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant.</p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0004 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, CYS72TRP
<br />
SNP: rs116840776,
gnomAD: rs116840776,
ClinVar: RCV000008769, RCV000024381, RCV000150236, RCV000171752, RCV000249612, RCV000477819, RCV000769171, RCV000987087, RCV001084478, RCV001144018, RCV003952349
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (C72W) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation CYS71TRP. </p><p>In 1 of 82 patients with muscular dystrophy (see RMD2; 606072), McNally et al. (1998) identified a heterozygous C-to-G change in the CAV3 gene, resulting in a cys71-to-trp (C71W) substitution. The patient had progressive proximal muscle weakness beginning in the first decade, but remained ambulatory in the mid-second decade. Her mother and 2 siblings had the identical missense change, but did not have symptoms of muscular dystrophy, suggesting that a single abnormal allele is not sufficient to cause the phenotype and that the likely inheritance is autosomal recessive. The authors were unable to determine the nature of the second allele in the proband. The mutation was not identified in 200 control chromosomes. McNally (1998) suspected that the phenotype was the result of either loss-of-function mutations or dominant-negative mutations; she doubted that haploinsufficiency leads to the disease. The family was lost to follow-up. </p><p>Among 100 normal Brazilian control subjects, de Paula et al. (2001) identified heterozygosity for the C71W change in 1 subject. They concluded that C71W is a rare polymorphism that does not cause an abnormal phenotype when present in just one allele. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0005 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED
</span>
</div>
<div>
<span class="mim-text-font">
CAV3, ALA46THR
<br />
SNP: rs116840789,
ClinVar: RCV000008772, RCV000008774, RCV000024382, RCV001384920, RCV002381245, RCV004585993
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (A46T) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ALA45THR. </p><p>In a 4-year-old girl presenting with myalgia and muscle cramps diagnosed as limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Herrmann et al. (2000) identified a heterozygous 136G-to-A change, resulting in an ala46-to-thr substitution. The mutation prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. </p><p>In 2 unrelated families with rippling muscle disease from Germany, reported by Vorgerd et al. (1999), and the first-described RMD family from Norway, reported by Torbergsen (1975), Betz et al. (2001) identified a heterozygous mutation in the CAV3 gene, resulting in an ala45-to-thr substitution (A45T). A muscle biopsy from a patient carrying the mutation showed decreased surface expression of the caveolin-3 protein. </p><p>Fulizio et al. (2005) identified the A46T mutation in 4 unrelated patients with decreased caveolin-3 on muscle biopsy. Three patients had myalgia and/or mild proximal muscle weakness, whereas 1 was diagnosed with LGMD1C. Three of the patients had a positive family history of muscle-related disorders. The father and 2 paternal uncles of 1 patient with mild muscle weakness were reportedly asymptomatic with elevated serum creatine kinase (123320). Skeletal muscle caveolin-3 protein in the 4 probands ranged from less than 5 to 10%. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0006 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, ALA46VAL
<br />
SNP: rs116840773,
ClinVar: RCV000008775, RCV000024383
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (A46V) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ALA45VAL. </p><p>In family B with rippling muscle disease (RMD2; 606072) described by Ricker et al. (1989), Betz et al. (2001) identified a mutation in the CAV3 gene, resulting in an ala45-to-val (A45V) substitution. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0007 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED<br />
MYOPATHY, DISTAL, TATEYAMA TYPE, INCLUDED
</span>
</div>
<div>
<span class="mim-text-font">
CAV3, ARG27GLN
<br />
SNP: rs116840778,
ClinVar: RCV000008777, RCV000008778, RCV000023083, RCV000408119, RCV000527324, RCV002490340
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ARG26GLN. </p><p>In kindred B with autosomal dominant rippling muscle disease (RMD2; 606072) described by Vorgerd et al. (1999), Betz et al. (2001) identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. </p><p>In a patient with sporadic rippling muscle disease, Vorgerd et al. (2001) identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. Vorgerd et al. (2001) suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. </p><p>In a 71-year-old woman with a diagnosis of limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Figarella-Branger et al. (2003) identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. Figarella-Branger et al. (2003) emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. </p><p>Carbone et al. (2000) identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; 123320) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Carbone et al. (2000) concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. </p><p>In a Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; 614321), Tateyama et al. (2002) identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin (603009) immunoreactivity. Tateyama et al. (2002) noted the unusual clinical phenotype of the patient. </p><p>Gonzalez-Perez et al. (2009) identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. Gonzalez-Perez et al. (2009) noted the variable phenotypic features in this family. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0008 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, ASP28GLU
<br />
SNP: rs116840782,
ClinVar: RCV000008770, RCV000024386
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (D28E) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ASP27GLU. </p><p>In 9 affected members of a large German family with autosomal dominant rippling muscle disease (RMD2; 606072), Fischer et al. (2003) identified a heterozygous C-A change in exon 1 of the CAV3 gene, resulting in an asp27-to-glu (D27E) substitution within the N terminus of the protein. The mutation was not detected in 10 unaffected family members or in 200 normal control chromosomes. Five of the 9 patients had additional signs of a distal myopathy with ankle and hand weakness and atrophy. Two other patients had predominantly proximal muscle weakness and were diagnosed with limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease. The 2 youngest patients showed only isolated signs of rippling muscle disease without muscle weakness or atrophy. Immunohistochemical and Western blot analysis showed a severe reduction of CAV3 protein expression in skeletal muscle from the index patient, supporting a dominant-negative effect of the mutation. The authors commented on the marked intrafamilial clinical variability caused by the mutation. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0009 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, LEU87PRO
<br />
SNP: rs28936685,
gnomAD: rs28936685,
ClinVar: RCV000008779, RCV000024387, RCV000458893, RCV001787372, RCV003352748
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (L87P) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation LEU86PRO. </p><p>In a Colombian patient with severe rippling muscle disease (RMD2; 606072), Kubisch et al. (2003) identified a homozygous 215T-C transition in the CAV3 gene, resulting in a leu86-to-pro substitution (L86P) in the membrane-associated domain of the protein. The patient had muscle stiffness in his legs since the age of 3 years and contractures of the Achilles tendon leading to gait disturbances. At age 20, he had elevated creatine kinase levels, hypertrophic skeletal muscles, and generalized rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin (603009). The patient did not have family members available for further study, so it could not be determined if the mutation represented autosomal recessive RMD. Kubisch et al. (2003) noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies are part of a clinical continuum. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0010 &nbsp; RIPPLING MUSCLE DISEASE 2, AUTOSOMAL RECESSIVE</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, ALA93THR
<br />
SNP: rs28936686,
gnomAD: rs28936686,
ClinVar: RCV000008780, RCV000024388, RCV000234612, RCV000622234, RCV000826098, RCV005031426
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (A93T) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ALA92THR. </p><p>In an Italian patient with severe rippling muscle disease (RMD2; 606072), Kubisch et al. (2003) identified a homozygous 232G-A transition in the CAV3 gene, resulting in an ala92-to-thr substitution (A92T) in the membrane-associated domain of the protein. The patient had slowly progressive muscle weakness beginning in early adulthood, elevated creatine kinase, and rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin (603009). Kubisch et al. (2003) noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies are part of a clinical continuum. </p><p>Kubisch et al. (2005) identified homozygosity for the A92T mutation in 2 German sibs with childhood-onset of rippling muscle disease. Both unaffected parents were heterozygous for the mutation. The findings indicated that there is a form of autosomal recessive RMD in which heterozygous carriers do not manifest the disease. Haplotype analysis indicated that the mutation arose independently from the mutation observed in the Italian patient reported by Kubisch et al. (2003), suggesting that A92T is a mutation hotspot. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0011 &nbsp; CREATINE PHOSPHOKINASE, ELEVATED SERUM</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
RIPPLING MUSCLE DISEASE 2, INCLUDED
</span>
</div>
<div>
<span class="mim-text-font">
CAV3, 3-BP DEL, PHE98DEL
<br />
SNP: rs116840802, rs199476335,
ClinVar: RCV000008781, RCV000008782, RCV000024390, RCV004786247
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation PHE97DEL. </p><p>Cagliani et al. (2003) reported a multigenerational Italian family with deletion of nucleotides 328-330 in the CAV3 gene, resulting in deletion of phenylalanine at codon 97. All members with the mutation had elevated serum creatine kinase (123320), but there was remarkable intrafamilial variation in other features, including rippling muscle disease (RMD2; 606072), proximal limb weakness, distal limb weakness, and what was considered to be a more severe limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease. Muscle biopsy of 3 affected patients showed myopathic changes and a deficiency of caveolin-3 by immunostaining and Western blot analysis. A heart biopsy in 1 patient showed that caveolin-3 was present at approximately 60% of the normal level. Cagliani et al. (2003) noted that the findings provided an explanation of why heart involvement is not a feature of caveolinopathies, and suggested that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0012 &nbsp; CREATINE PHOSPHOKINASE, ELEVATED SERUM</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, PRO29LEU
<br />
SNP: rs116840786,
gnomAD: rs116840786,
ClinVar: RCV000008784, RCV000024389, RCV003531900
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (P29L) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation PRO28LEU. </p><p>In an 18-year-old man and his mother with isolated persistent hyperCKemia (123320), Merlini et al. (2002) identified a heterozygous 83C-T transition in exon 1 of the CAV3 gene, resulting in a pro28-to-leu (P28L) substitution. Muscle biopsy showed partial CAV3 deficiency, but neither patient had any signs or symptoms of myopathy. The mutation was not found in 50 patients with different myopathies or in 100 normal controls. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0013 &nbsp; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, THR64SER
<br />
SNP: rs116840799, rs121909280,
ClinVar: RCV000008785, RCV000024395, RCV001150160
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (T64S) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation THR63SER. </p><p>In 2 Japanese brothers with hypertrophic cardiomyopathy (CMH1; 192600) whose father had hypertrophic cardiomyopathy and had died suddenly at the age of 41 years, Hayashi et al. (2004) identified a thr63-to-ser (T63S) mutation in the CAV3 gene. The threonine at codon 63 is evolutionarily conserved in the scaffolding domain of caveolin-3. Two mutations involving codon 63 had earlier been reported, T63P and deletion of 3 amino acids at positions 63-65 (601253.0002), in patients diagnosed with LGMD1C. Hayashi et al. (2004) stated that the clinical findings of the index patient with the T63S mutation was mild. At the age of 16, he showed marginal concentric left ventricular hypertrophy and his left ventricular end-diastolic pressure was high in catheterization studies. His electrocardiogram showed high voltage. After 9 years' follow-up, left ventricular wall thickness was not changed markedly, but dilatation of the left ventricular and systolic dimension were increased. Similar phenotypes were found in his brother. Both of them as well as their father had no symptoms of skeletal muscle disorder and no elevation of serum creatine kinase, suggesting that they were not affected with LGMD, rippling muscle disease, or hyperCKemia. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0014 &nbsp; MYOPATHY, DISTAL, TATEYAMA TYPE</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, ASN33LYS
<br />
SNP: rs1008642,
gnomAD: rs1008642,
ClinVar: RCV000008786, RCV001212042
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a mother and daughter with distal myopathy and absence of caveolin-3 protein (MPDT; 614321) on skeletal muscle biopsy, Fulizio et al. (2005) identified a heterozygous 99C-G transversion in exon 1 of the CAV3 gene, resulting in an asn33-to-lys (N33K) substitution in the N-terminal domain of the protein. Ages at onset were 30 and 27 years, respectively. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0015 &nbsp; RIPPLING MUSCLE DISEASE 2</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, GLU47LYS
<br />
SNP: rs116840793,
ClinVar: RCV000008787, RCV000024416
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation (E47K) is based on the numbering system used by Fulizio et al. (2005). Other reports designated this mutation GLU46LYS. </p><p>In a father and son with rippling muscle disease (RMD2; 606072), Madrid et al. (2005) identified a heterozygous 136G-A transition in exon 2 of the CAV3 gene, resulting in a glu46-to-lys (E46K) substitution. Muscle biopsy from the father showed absence of caveolin-3 immunostaining. Unusual features in both these patients included congenital pes equinus deformity and early toe walking, which resolved after orthopedic surgical correction. In addition, the father had nonprogressive mild proximal muscle weakness, and the son demonstrated percussion-induced rapid contractions of the thenar muscles without overt rippling of other muscles. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0016 &nbsp; LONG QT SYNDROME 9</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, SER141ARG
<br />
SNP: rs104893713,
gnomAD: rs104893713,
ClinVar: RCV000008788, RCV000024432
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In a 16-year-old white male with nonexertional dyspnea and a QTc of 480 ms (LQT9; 611818) who was negative for mutations in known LQT genes, Vatta et al. (2006) identified heterozygosity for a de novo 423C-G transversion in the CAV3 gene, resulting in a ser141-to-arg (S141R) substitution at a conserved residue in the functional C-terminal domain. Consistent with his negative family history and normal screening ECGs among first-degree relatives, genetic testing confirmed that neither parent carried the mutation, which was also not found in more than 1,000 control alleles. Functional studies demonstrated that S141R-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0017 &nbsp; LONG QT SYNDROME 9, ACQUIRED, SUSCEPTIBILITY TO</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, PHE97CYS
<br />
SNP: rs104893714,
ClinVar: RCV000008789, RCV000024431
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In a 13-year-old asthmatic girl with long QT syndrome (LQT9; 611818) who was negative for mutations in known LQT genes, Vatta et al. (2006) identified heterozygosity for a de novo 290T-G transversion in the CAV3 gene, resulting in a phe97-to-cys (F97C) substitution at a highly conserved residue in the transmembrane domain. The patient presented with shortness of breath and chest pain; ECG showed marked QT prolongation with a QTc of 532 ms, which was present only, but reproducibly, on beta-agonist inhaler therapy for her asthma. The family history was unremarkable, and screening ECGs in all first-degree relatives showed normal QTc. The mutation was not found in either of her parents or in more than 1,000 control alleles. Functional studies demonstrated that F97C-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0018 &nbsp; LONG QT SYNDROME 9</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
LONG QT SYNDROME 2/9, DIGENIC, INCLUDED
</span>
</div>
<div>
<span class="mim-text-font">
CAV3, THR78MET
<br />
SNP: rs72546668,
gnomAD: rs72546668,
ClinVar: RCV000008790, RCV000008791, RCV000024406, RCV000039801, RCV000168328, RCV000242756, RCV000769173, RCV000987088, RCV001144019, RCV003924817, RCV004764897
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In 3 unrelated individuals with long QT syndrome (LQT9; 611818), Vatta et al. (2006) identified heterozygosity for a 233C-T transition in the CAV3 gene, resulting in a thr78-to-met (T78M) substitution at a highly conserved residue. All 3 patients had a positive family history, but family members declined further genotyping. One patient had biallelic digenic mutations: she was a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, and was found to carry a A913V mutation in the LQT2-associated KCNH2 gene (152427.0024) as well as the T78M mutation. The other 2 patients, who were negative for mutations in other known LQTS genes, were an 8-year-old boy with nonexertional syncope and marked sinus bradycardia with a QTc of 433 ms and an asymptomatic 40-year-old male who had a QTc of 456 ms. The T78M mutation was not found in more than 1,000 control alleles. </p><p>In frozen necropsy tissue from a 2-month-old black female infant who died of sudden infant death syndrome (SIDS; 272120), Cronk et al. (2007) identified the T78M mutation in the CAV3 gene. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0019 &nbsp; LONG QT SYNDROME 9</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, ALA85THR
<br />
SNP: rs104893715,
ClinVar: RCV000008792, RCV000024430
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In a 36-year-old female who suffered a cardiac arrest while sleeping (LQT9; 611818), Vatta et al. (2006) identified heterozygosity for a 253G-A transition in the CAV3 gene, resulting in an ala85-to-thr (A85T) substitution at a conserved residue. The mutation was not found in more than 1,000 control alleles. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0020 &nbsp; LONG QT SYNDROME 9</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, VAL14LEU
<br />
SNP: rs121909281,
gnomAD: rs121909281,
ClinVar: RCV000008793, RCV000024433
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In frozen necropsy tissue from a 6-month-old black male infant who died of sudden infant death syndrome (SIDS; 272120), Cronk et al. (2007) identified a 40G-C transversion in the CAV3 gene, resulting in a val14-to-leu (V14L) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0021 &nbsp; LONG QT SYNDROME 9</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
CAV3, LEU79ARG
<br />
SNP: rs121909282,
gnomAD: rs121909282,
ClinVar: RCV000008794, RCV000024434, RCV001246513
</span>
</div>
<div>
<span class="mim-text-font">
<p>The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). </p><p>In frozen necropsy tissue from an 8-month-old black female infant who died of sudden infant death syndrome (SIDS; 272120), Cronk et al. (2007) identified a 236T-G transversion in the CAV3 gene, resulting in a leu79-to-arg (L79R) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. </p>
</span>
</div>
<div>
<br />
</div>
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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Galbiati, F., Volonte, D., Minetti, C., Chu, J. B., Lisanti, M. P.
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Garcia-Cardena, G., Martasek, P., Masters, B. S. S., Skidd, P. M., Couet, J. C., Li, S., Lisanti, M. P., Sessa, W. C.
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Gazzerro, E., Sotgia, F., Bruno, C., Lisanti, M. P., Minetti, C.
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Hagiwara, Y., Sasaoka, T., Araishi, K., Imamura, M., Yorifuji, H., Nonaka, I., Ozawa, E., Kikuchi, T.
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<p class="mim-text-font">
Hamosh, A.
<strong>Personal Communication.</strong>
Baltimore, Md. January 24, 2018.
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Hayashi, T., Arimura, T., Ueda, K., Shibata, H., Hohda, S., Takahashi, M., Hori, H., Koga, Y., Oka, N., Imaizumi, T., Yasunami, M., Kimura, A.
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Herrmann, R., Straub, V., Blank, M., Kutzick, C., Franke, N., Jacob, E. N., Lenard, H.-G., Kroger, S., Voit, T.
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Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M.
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Kuga, A., Ohsawa, Y., Okada, T., Kanda, F., Kanagawa, M., Toda, T., Sunada, Y.
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Madrid, R. E., Kubisch, C., Hays, A. P.
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Matsuda, C., Hayashi, Y. K., Ogawa, M., Aoki, M., Murayama, K., Nishino, I., Nonaka, I., Arahata, K., Brown, R. H., Jr.
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McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M.
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McNally, E. M.
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Merlini, L., Carbone, I., Capanni, C., Sabatelli, P., Tortorelli, S., Sotgia, F., Lisanti, M. P., Bruno, C., Minetti, C.
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Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F.
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Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G.
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Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y.
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Oshikawa, J., Otsu, K., Toya, Y., Tsunematsu, T., Hankins, R., Kawabe, J., Minamisawa, S., Umemura, S., Hagiwara, Y., Ishikawa, Y.
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Ricker, K., Moxley, R. T., Rohkamm, R.
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Sotgia, F., Minetti, C., Lisanti, M. P.
<strong>Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome.</strong>
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Straub, V., Murphy, A., Udd, B.
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Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T.
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<p class="mim-text-font">
Tang, Z., Scherer, P. E., Okamoto, T., Song, K., Chu, C., Kohtz, D. S., Nishimoto, I., Lodish, H. F., Lisanti, M. P.
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<p class="mim-text-font">
Tateyama, M., Aoki, M., Nishino, I., Hayashi, Y. K., Sekiguchi, S., Shiga, Y., Takahashi, T., Onodera, Y., Haginoya, K., Kobayashi, K., Iinuma, K., Nonaka, I., Arahata, K., Itoyama, Y.
<strong>Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.</strong>
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[PubMed: 11805270]
[Full Text: https://doi.org/10.1212/wnl.58.2.323]
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<li>
<p class="mim-text-font">
Torbergsen, T.
<strong>A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita Thomsen.</strong>
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[PubMed: 1146501]
[Full Text: https://doi.org/10.1111/j.1600-0404.1975.tb07603.x]
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<p class="mim-text-font">
Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A.
<strong>Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.</strong>
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[PubMed: 17060380]
[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.635268]
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<p class="mim-text-font">
Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W.
<strong>Phenotypic variability in rippling muscle disease.</strong>
Neurology 52: 1453-1459, 1999.
[PubMed: 10227634]
[Full Text: https://doi.org/10.1212/wnl.52.7.1453]
</p>
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<li>
<p class="mim-text-font">
Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W.
<strong>A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.</strong>
Neurology 57: 2273-2277, 2001.
[PubMed: 11756609]
[Full Text: https://doi.org/10.1212/wnl.57.12.2273]
</p>
</li>
</ol>
<div>
<br />
</div>
</div>
</div>
<div>
<div class="row">
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
<span class="text-nowrap mim-text-font">
Contributors:
</span>
</div>
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Patricia A. Hartz - updated : 4/10/2013<br>Cassandra L. Kniffin - updated : 11/1/2011<br>George E. Tiller - updated : 10/28/2008<br>Marla J. F. O&#x27;Neill - updated : 2/12/2008<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Cassandra L. Kniffin - updated : 12/7/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 1/31/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 4/27/2005<br>Cassandra L. Kniffin - updated : 2/17/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 10/6/2004<br>Cassandra L. Kniffin - updated : 8/30/2004<br>Cassandra L. Kniffin - updated : 2/3/2004<br>Cassandra L. Kniffin - updated : 1/20/2004<br>Cassandra L. Kniffin - updated : 6/6/2003<br>Cassandra L. Kniffin - reorganized : 5/22/2003<br>Cassandra L. Kniffin - updated : 5/8/2003<br>Cassandra L. Kniffin - updated : 12/30/2002<br>George E. Tiller - updated : 1/23/2002<br>Ada Hamosh - updated : 6/27/2001<br>George E. Tiller - updated : 4/13/2001<br>George E. Tiller - updated : 3/5/2001<br>George E. Tiller - updated : 12/14/2000<br>Victor A. McKusick - updated : 9/26/2000<br>Victor A. McKusick - updated : 10/26/1999<br>Victor A. McKusick - updated : 3/12/1999<br>Victor A. McKusick - updated : 5/22/1998<br>Victor A. McKusick - updated : 3/31/1998
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Mark H. Paalman : 5/9/1996
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carol : 06/03/2024<br>carol : 11/01/2022<br>carol : 07/24/2019<br>carol : 09/27/2018<br>carol : 09/26/2018<br>carol : 09/25/2018<br>carol : 04/25/2018<br>carol : 04/18/2018<br>carol : 03/27/2017<br>carol : 09/16/2016<br>mgross : 04/10/2013<br>mgross : 4/10/2013<br>carol : 3/21/2013<br>mgross : 3/13/2013<br>terry : 10/4/2012<br>terry : 11/1/2011<br>carol : 11/1/2011<br>ckniffin : 11/1/2011<br>carol : 1/13/2011<br>alopez : 2/9/2009<br>wwang : 10/28/2008<br>carol : 7/9/2008<br>carol : 7/9/2008<br>carol : 3/10/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>wwang : 7/20/2007<br>wwang : 2/9/2007<br>ckniffin : 2/5/2007<br>wwang : 12/11/2006<br>ckniffin : 12/7/2006<br>wwang : 3/9/2006<br>terry : 2/17/2006<br>wwang : 2/6/2006<br>terry : 1/31/2006<br>wwang : 12/9/2005<br>terry : 12/7/2005<br>terry : 8/3/2005<br>wwang : 5/10/2005<br>ckniffin : 4/27/2005<br>wwang : 2/21/2005<br>ckniffin : 2/17/2005<br>ckniffin : 2/17/2005<br>wwang : 2/16/2005<br>wwang : 2/11/2005<br>terry : 2/4/2005<br>alopez : 10/7/2004<br>terry : 10/6/2004<br>carol : 9/7/2004<br>ckniffin : 8/30/2004<br>tkritzer : 2/9/2004<br>ckniffin : 2/3/2004<br>tkritzer : 1/23/2004<br>ckniffin : 1/20/2004<br>carol : 6/6/2003<br>ckniffin : 6/2/2003<br>carol : 5/22/2003<br>ckniffin : 5/20/2003<br>ckniffin : 5/20/2003<br>ckniffin : 5/16/2003<br>carol : 5/16/2003<br>ckniffin : 5/8/2003<br>cwells : 1/7/2003<br>ckniffin : 12/30/2002<br>terry : 3/28/2002<br>cwells : 2/13/2002<br>cwells : 1/23/2002<br>carol : 6/29/2001<br>carol : 6/29/2001<br>mgross : 6/29/2001<br>mgross : 6/28/2001<br>mgross : 6/28/2001<br>terry : 6/27/2001<br>cwells : 5/4/2001<br>cwells : 4/25/2001<br>cwells : 4/13/2001<br>cwells : 3/6/2001<br>cwells : 3/5/2001<br>cwells : 3/2/2001<br>cwells : 1/16/2001<br>terry : 12/14/2000<br>mcapotos : 10/6/2000<br>mcapotos : 10/3/2000<br>terry : 9/26/2000<br>terry : 2/28/2000<br>carol : 11/3/1999<br>terry : 10/26/1999<br>terry : 5/20/1999<br>carol : 3/15/1999<br>terry : 3/12/1999<br>carol : 2/10/1999<br>terry : 6/3/1998<br>terry : 5/22/1998<br>joanna : 5/15/1998<br>alopez : 4/8/1998<br>alopez : 4/1/1998<br>terry : 3/31/1998<br>carol : 3/21/1998<br>jamie : 5/29/1997<br>mark : 5/13/1996<br>mark : 5/10/1996<br>mark : 5/9/1996<br>mark : 5/9/1996
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