4031 lines
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Entry
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- *103950 - ALPHA-2-MACROGLOBULIN; A2M
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*103950</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/103950">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000175899;t=ENST00000318602" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=103950" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000175899;t=ENST00000318602" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000014,NM_001347423,NM_001347424,NM_001347425,XM_006719056" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000014" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=103950" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00072&isoform_id=00072_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/A2M" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/24761,177870,177872,825615,13661814,13661816,25303946,45708661,46812315,51476396,62088808,119608996,308153640,440575713,578822814,1677538581,1779421278,1779421317,1779421328,2029084499,2029084501,2029084503,2029084505,2029084507,2029084509,2029084511,2029084513,2029084515,2029084517,2029084519,2029084521,2029084523,2029084525,2029084527,2029084529,2029084531,2029084533,2029084535,2029084537,2029084539,2029084541,2029084543,2029084545,2029084547,2029084549,2029084551,2029084553,2029084555,2462530589" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P01023" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000175899;t=ENST00000318602" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=A2M" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=A2M" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/A2M" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr12&hgg_gene=ENST00000318602.12&hgg_start=9067708&hgg_end=9116229&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=103950[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=103950[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000175899" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=A2M" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=A2M" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=A2M" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=A2M&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA24357" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:7" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2449119" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/A2M#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:2449119" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=A2M&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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103950
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</span>
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</span>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ALPHA-2-MACROGLOBULIN; A2M
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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MACROGLOBULIN, ALPHA-2
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</span>
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</h4>
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<div>
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<br />
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</div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=A2M" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">A2M</a></em></strong>
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</span>
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</p>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/12/121?start=-3&limit=10&highlight=121">12p13.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:9067708-9116229&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'})">12:9,067,708-9,116,229</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A2M is a 718-kD homotetrameric glycoprotein of plasma and extracellular spaces that was first recognized as a broad spectrum protease inhibitor. A2M is activated by proteases with which it interacts, and this proteolytic activation causes a conformational change that traps the protease within the A2M homotetramer. In addition, A2M contains several independent domains that function as carriers of specific growth factors and/or binding sites for receptors. Activation of A2M by proteases alters the interaction of A2M with these ligands and induces cell signaling (summary by <a href="#17" class="mim-tip-reference" title="Mantuano, E., Mukandala, G., Li, X., Campana, W. M., Gonias, S. L. <strong>Molecular dissection of the human alpha-2-macroglobulin subunit reveals domains with antagonistic activities in cell signaling.</strong> J. Biol. Chem. 283: 19904-19911, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18499670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18499670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18499670[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801762200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18499670">Mantuano et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18499670" 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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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Using synthetic oligonucleotides as hybridization probes, <a href="#14" class="mim-tip-reference" title="Kan, C.-C., Solomon, E., Belt, K. T., Chain, A. C., Hiorns, L. R., Fey, G. <strong>Nucleotide sequence of cDNA encoding human alpha-2-macroglobulin and assignment of the chromosomal locus.</strong> Proc. Nat. Acad. Sci. 82: 2282-2286, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2581245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2581245</a>] [<a href="https://doi.org/10.1073/pnas.82.8.2282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2581245">Kan et al. (1985)</a> isolated A2M cDNA clones from a human liver cDNA library. The coding sequence predicted a 1,451-amino acid polypeptide. Human A2M is a tetramer of 4 identical 185-kD subunits arranged as a pair of dimers, each consisting of 2 disulfide-linked monomers. The protein has a bait region composed of peptide bonds for plasma proteases and a thiol ester bond which, when hydrolyzed, leads to covalent bonding between the protease and A2M. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2581245" 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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</span>
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<div>
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<div class="mim-changed mim-change"><p><a href="#20" class="mim-tip-reference" title="Matthijs, G., Devriendt, K., Cassiman, J.-J., van den Berghe, H., Marynen, P. <strong>Structure of the human alpha-2 macroglobulin gene and its promotor (sic).</strong> Biochem. Biophys. Res. Commun. 184: 596-603, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1374237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1374237</a>] [<a href="https://doi.org/10.1016/0006-291x(92)90631-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1374237">Matthijs et al. (1992)</a> demonstrated that the A2M gene spans approximately 48 kb and has 36 exons, from 21 to 229 bp in size and with consensus splice sites. Intron sizes range from 125 bp to 7.5 kb. The A2M gene is present in single copy in the haploid genome. <a href="#29" class="mim-tip-reference" title="Umans, L., Serneels, L., Hilliker, C., Stas, L., Overbergh, L., De Strooper, B., Van Leuven, F., Van den Berghe, H. <strong>Molecular cloning of the mouse gene coding for alpha-2-macroglobulin and targeting of the gene in embryonic stem cells.</strong> Genomics 22: 519-529, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7528166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7528166</a>] [<a href="https://doi.org/10.1006/geno.1994.1425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7528166">Umans et al. (1994)</a> found that the homologous gene in the mouse contains 36 exons, coding for a 4.8-kb cDNA. Including putative control elements in the 5-prime flanking region, the gene covers about 45 kb. The promoter region of the mouse A2m gene differed considerably from the known promoter sequences of the human and rat genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1374237+7528166" 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></div>
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<p><a href="#14" class="mim-tip-reference" title="Kan, C.-C., Solomon, E., Belt, K. T., Chain, A. C., Hiorns, L. R., Fey, G. <strong>Nucleotide sequence of cDNA encoding human alpha-2-macroglobulin and assignment of the chromosomal locus.</strong> Proc. Nat. Acad. Sci. 82: 2282-2286, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2581245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2581245</a>] [<a href="https://doi.org/10.1073/pnas.82.8.2282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2581245">Kan et al. (1985)</a> assigned the A2M locus to chromosome 12 by Southern blot analysis of DNA from a panel of mouse/human somatic cell hybrids, using A2M cDNA as a hybridization probe. <a href="#11" class="mim-tip-reference" title="Fukushima, Y., Bell, G. I., Shows, T. B. <strong>The polymorphic human alpha-2-macroglobulin gene (A2M) is located in chromosome region 12p12.3-p13.3.</strong> Cytogenet. Cell Genet. 48: 58-59, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2460294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2460294</a>] [<a href="https://doi.org/10.1159/000132587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2460294">Fukushima et al. (1988)</a> assigned the A2M locus to 12p13.3-p12.3 by in situ hybridization. Assignment of the A2M gene to human chromosome 12p13-p12.2 was confirmed by <a href="#19" class="mim-tip-reference" title="Marynen, P., Zhang, J., Devriendt, K., Cassiman, J.-J. <strong>Alpha-2-macroglobulin, pregnancy zone protein and an alpha-2-macroglobulin pseudogene map to chromosome 12p12.2-p13. (Abstract)</strong> Cytogenet. Cell Genet. 51: 1040 only, 1989."None>Marynen et al. (1989)</a> by use of in situ hybridization and somatic cell hybrid DNA analysis. <a href="#8" class="mim-tip-reference" title="Devriendt, K., Zhang, J., van Leuven, F., van den Berghe, H., Cassiman, J. J., Marynen, P. <strong>A cluster of alpha 2-macroglobulin-related genes (alpha 2 M) on human chromosome 12p: cloning of the pregnancy-zone protein gene and an alpha 2M pseudogene.</strong> Gene 81: 325-334, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2478422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2478422</a>] [<a href="https://doi.org/10.1016/0378-1119(89)90193-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2478422">Devriendt et al. (1989)</a> also assigned A2M to 12p13-p12 by analysis of somatic cell hybrids and in situ hybridization. They showed, furthermore, that a closely related gene for pregnancy-zone protein (PZP; <a href="/entry/176420">176420</a>) and an A2M pseudogene map to the same region. <a href="#13" class="mim-tip-reference" title="Hilliker, C., Overbergh, L., Petit, P., Van Leuven, F., Van den Berghe, H. <strong>Assignment of mouse alpha-2-macroglobulin gene to chromosome 6 band F1-G3.</strong> Mammalian Genome 3: 469-471, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1379499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1379499</a>] [<a href="https://doi.org/10.1007/BF00356160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1379499">Hilliker et al. (1992)</a> showed that the gene is located on mouse chromosome 6 band F1-G3 in a syntenic group that has its human counterpart on 12p13-p12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1379499+2581245+2478422+2460294" 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>Alpha-2-macroglobulin is, like alpha-1-antitrypsin, alpha-2-antiplasmin, and antithrombin III, a protease inhibitor. It inhibits many proteases, including trypsin, thrombin, and collagenase (<a href="#3" class="mim-tip-reference" title="Bergqvist, D., Nilsson, I. M. <strong>Hereditary alpha-2-macroglobulin deficiency.</strong> Scand. J. Haemat. 23: 433-436, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/94459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">94459</a>]" pmid="94459">Bergqvist and Nilsson, 1979</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=94459" 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="Mantuano, E., Mukandala, G., Li, X., Campana, W. M., Gonias, S. L. <strong>Molecular dissection of the human alpha-2-macroglobulin subunit reveals domains with antagonistic activities in cell signaling.</strong> J. Biol. Chem. 283: 19904-19911, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18499670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18499670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18499670[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801762200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18499670">Mantuano et al. (2008)</a> used isolated recombinant human A2M protein fragments, which they called FP3 and FP6, to characterize the cellular functions of specific A2M domains. FP3 contains residues 591 to 774 of A2M and includes the growth factor carrier sites, and FP6 contains residues 1242 to 1451 of A2M and includes the LRP1 (<a href="/entry/107770">107770</a>) recognition domain. FP6 rapidly and robustly activated Akt (see <a href="/entry/164730">164730</a>) and Erk/MAP kinases (see <a href="/entry/176948">176948</a>) in cultured rat Schwann cells and PC12 rat pheochromocytoma cells. FP6 also promoted neurite outgrowth and expression of Gap43 (<a href="/entry/162060">162060</a>). These cell signaling events were mediated by Lrp1 and depended on 2 lysines in FP6 that were required for Lrp1 binding. The ability of FP6 to trigger Lrp1-dependent cell signaling in PC12 cells was reproduced by a purified 18-kD fragment of human plasma A2M that included the LRP1 recognition domain. FP3 alone did not induce cell signaling in rat Schwann and PC12 cells, but it blocked Ngf-beta (NGFB; <a href="/entry/162030">162030</a>)-induced activation of Akt and Erk/MAP kinases. FP3 did not block activation of cell signaling induced by FP6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18499670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mass spectrometry, <a href="#22" class="mim-tip-reference" title="Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L.-H., Rahmanto, Y. S., Richardson, D. R., Vyoral, D. <strong>Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.</strong> Blood 113: 6225-6236, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380872</a>] [<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380872">Peslova et al. (2009)</a> showed that hepcidin (HAMP; <a href="/entry/606464">606464</a>) in human plasma or serum was bound by albumin (ALB; <a href="/entry/103600">103600</a>) and by A2M. Binding of hepcidin to albumin was nonspecific and displayed nonsaturable kinetics. However, binding of hepcidin to A2M was specific. Scatchard analysis estimated 2 hepcidin-binding sites per inactive A2M molecule. Proteolytic activation of A2M resulted in a sigmoidal binding curve, suggesting high-affinity cooperative allosteric binding of 4 hepcidin molecules per active A2M molecule. The hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased ferroportin (SLC40A1; <a href="/entry/604653">604653</a>) expression in J774 murine macrophages more effectively than hepcidin alone. <a href="#22" class="mim-tip-reference" title="Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L.-H., Rahmanto, Y. S., Richardson, D. R., Vyoral, D. <strong>Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.</strong> Blood 113: 6225-6236, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380872</a>] [<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380872">Peslova et al. (2009)</a> hypothesized that A2M has a role in regulating hepcidin action by sequestration and subsequent release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380872" 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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---Alpha-2-Macroglobulin Deficiency</p><p>By the electroimmunoassay of Laurell, <a href="#3" class="mim-tip-reference" title="Bergqvist, D., Nilsson, I. M. <strong>Hereditary alpha-2-macroglobulin deficiency.</strong> Scand. J. Haemat. 23: 433-436, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/94459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">94459</a>]" pmid="94459">Bergqvist and Nilsson (1979)</a> found alpha-2-macroglobulin deficiency (<a href="/entry/614036">614036</a>) in a 37-year-old man, his mother, and one daughter. The deficient persons were apparently heterozygotes. No clinical disadvantage resulted from the deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=94459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Poller, W., Barth, J., Voss, B. <strong>Detection of an alteration of the alpha-2-macroglobulin gene in a patient with chronic lung disease and serum alpha-2-macroglobulin deficiency.</strong> Hum. Genet. 83: 93-96, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475424</a>] [<a href="https://doi.org/10.1007/BF00274157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475424">Poller et al. (1989)</a> detected an alteration in the A2M gene in a patient with serum A2M deficiency and chronic lung disease since childhood. The alteration involved restriction sites detected with 10 different enzymes and was thought to have been caused by major deletion or rearrangement in the gene. Nine of the restriction enzymes used detected no polymorphism in 40 healthy control subjects and 39 patients with chronic obstructive pulmonary disease. The patient was heterozygous for the A2M alteration; <a href="#23" class="mim-tip-reference" title="Poller, W., Barth, J., Voss, B. <strong>Detection of an alteration of the alpha-2-macroglobulin gene in a patient with chronic lung disease and serum alpha-2-macroglobulin deficiency.</strong> Hum. Genet. 83: 93-96, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475424</a>] [<a href="https://doi.org/10.1007/BF00274157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475424">Poller et al. (1989)</a> suggested that this was responsible for the pulmonary disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2475424" 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>---Alzheimer Disease</p><p>Alpha-2-macroglobulin has been implicated in Alzheimer disease (AD; see <a href="/entry/104300">104300</a>) based on its ability to mediate the clearance and degradation of A-beta, the major component of amyloid beta deposits. <a href="#6" class="mim-tip-reference" title="Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E. <strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong> Nature Genet. 19: 357-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>] [<a href="https://doi.org/10.1038/1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697696">Blacker et al. (1998)</a> analyzed a deletion in the A2M gene (<a href="#0005">103950.0005</a>) at the 5-prime splice site of 'exon II' of the bait region (exon 18) and found that inheritance of the deletion, designated A2M-2, conferred increased risk for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD. These values were comparable to those obtained for the APOE4 allele in the same sample, but in contrast to APOE4, A2M-2 did not affect age of onset. The observed association that A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which <a href="#6" class="mim-tip-reference" title="Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E. <strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong> Nature Genet. 19: 357-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>] [<a href="https://doi.org/10.1038/1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697696">Blacker et al. (1998)</a> were unable to confirm in their sample. Thus, A2M, the A2M receptor (LRP1; <a href="/entry/107770">107770</a>), and the genes for 2 other LRP (low density lipoprotein-related protein) ligands, APOE (<a href="/entry/107741">107741</a>) and APP (<a href="/entry/104760">104760</a>), had all been genetically linked to AD, suggesting that these proteins may participate in the common neuropathogenic pathway leading to the disease. <a href="#16" class="mim-tip-reference" title="Liao, A., Nitsch, R. M., Greenberg, S. M., Finckh, U., Blacker, D., Albert, M., Rebeck, G. W., Gomez-Isla, T., Clatworthy, A., Binetti, G., Hock, C., Mueller-Thomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J. H., Tanzi, R. E., Hyman, B. T. <strong>Genetic association of an alpha-2-macroglobulin (val1000ile) polymorphism and Alzheimer's disease.</strong> Hum. Molec. Genet. 7: 1953-1956, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811940</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811940">Liao et al. (1998)</a> found an association between the val1000-to-ile polymorphism (<a href="#0001">103950.0001</a>) and AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9811940+9697696" 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 study of AD in 3 samples of patients in the U.K., <a href="#9" class="mim-tip-reference" title="Dow, D. J., Lindsey, N., Cairns, N. J., Brayne, C., Robinson, D., Huppert, F. A., Paykel, E. S., Xuereb, J., Wilcock, G., Whittaker, J. L., Rubinsztein, D. C. <strong>Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK. (Letter)</strong> Nature Genet. 22: 16-17, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319853</a>] [<a href="https://doi.org/10.1038/8724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319853">Dow et al. (1999)</a> failed to show a strong association between A2M-2 and AD risk. <a href="#26" class="mim-tip-reference" title="Rudrasingham, V., Wavrant-De Vrieze, F., Lambert, J.-C., Chakraverty, S., Kehoe, P., Crook, R., Amouyel, P., Wu, W., Rice, F., Perez-Tur, J., Frigard, B., Morris, J. C., and 11 others. <strong>Alpha-2 macroglobulin gene and Alzheimer disease. (Letter)</strong> Nature Genet. 22: 17-19, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319854</a>] [<a href="https://doi.org/10.1038/8726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319854">Rudrasingham et al. (1999)</a> did not find associations between AD and A2M-2, or genotypes containing A2M-2, in a powerful, case-control sample. Using the same family-based association methods employed by <a href="#6" class="mim-tip-reference" title="Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E. <strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong> Nature Genet. 19: 357-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>] [<a href="https://doi.org/10.1038/1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697696">Blacker et al. (1998)</a>, <a href="#25" class="mim-tip-reference" title="Rogaeva, E. A., Premkumar, S., Grubber, J., Serneels, L., Scott, W. K., Kawarai, T., Song, Y., Hill, D. M., Abou-Donia, S. M., Martin, E. R., Vance, J. J., Yu, G., and 18 others. <strong>An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. (Letter)</strong> Nature Genet. 22: 19-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319855</a>] [<a href="https://doi.org/10.1038/8729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319855">Rogaeva et al. (1999)</a> also could not replicate the association of A2M-2 in 2 comparable, independent familial AD datasets or in a larger dataset of families from the same dataset tested by <a href="#6" class="mim-tip-reference" title="Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E. <strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong> Nature Genet. 19: 357-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>] [<a href="https://doi.org/10.1038/1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697696">Blacker et al. (1998)</a>. Furthermore, they were unable to document any biologic effect of the A2M-2 allele on A2M RNA splicing, protein monomeric molecular mass, or protein levels in brain, liver, or plasma of A2M-2 carriers. <a href="#25" class="mim-tip-reference" title="Rogaeva, E. A., Premkumar, S., Grubber, J., Serneels, L., Scott, W. K., Kawarai, T., Song, Y., Hill, D. M., Abou-Donia, S. M., Martin, E. R., Vance, J. J., Yu, G., and 18 others. <strong>An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. (Letter)</strong> Nature Genet. 22: 19-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319855</a>] [<a href="https://doi.org/10.1038/8729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319855">Rogaeva et al. (1999)</a> concluded that prior genetic evidence for an AD susceptibility locus on chromosome 12 likely arose from genetic variations other than in A2M-2 alleles. In a reply to these criticisms, <a href="#5" class="mim-tip-reference" title="Blacker, D., Crystal, A. S., Wilcox, M. A., Laird, N. M., Tanzi, R. E. <strong>Reply to Rudrasingham et al. (Letter)</strong> Nature Genet. 22: 21-22, 1999."None>Blacker et al. (1999)</a> commented that they did not find it surprising that the case-control studies conducted by the groups of <a href="#26" class="mim-tip-reference" title="Rudrasingham, V., Wavrant-De Vrieze, F., Lambert, J.-C., Chakraverty, S., Kehoe, P., Crook, R., Amouyel, P., Wu, W., Rice, F., Perez-Tur, J., Frigard, B., Morris, J. C., and 11 others. <strong>Alpha-2 macroglobulin gene and Alzheimer disease. (Letter)</strong> Nature Genet. 22: 17-19, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319854</a>] [<a href="https://doi.org/10.1038/8726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319854">Rudrasingham et al. (1999)</a>, <a href="#25" class="mim-tip-reference" title="Rogaeva, E. A., Premkumar, S., Grubber, J., Serneels, L., Scott, W. K., Kawarai, T., Song, Y., Hill, D. M., Abou-Donia, S. M., Martin, E. R., Vance, J. J., Yu, G., and 18 others. <strong>An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. (Letter)</strong> Nature Genet. 22: 19-21, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319855</a>] [<a href="https://doi.org/10.1038/8729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319855">Rogaeva et al. (1999)</a>, and <a href="#9" class="mim-tip-reference" title="Dow, D. J., Lindsey, N., Cairns, N. J., Brayne, C., Robinson, D., Huppert, F. A., Paykel, E. S., Xuereb, J., Wilcock, G., Whittaker, J. L., Rubinsztein, D. C. <strong>Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK. (Letter)</strong> Nature Genet. 22: 16-17, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319853</a>] [<a href="https://doi.org/10.1038/8724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319853">Dow et al. (1999)</a> could not find an association. They suggested that the findings highlighted differences between family-based and case-control association studies. In an accompanying editorial (<a href="#1" class="mim-tip-reference" title="Anonymous. <strong>Freely associating. (Editorial)</strong> Nature Genet. 22: 1-2, 1999."None>Anonymous, 1999</a>), the editor of Nature Genetics pointed out the difficulties in evaluating the results of association studies. Unresolved fundamental issues included such matters as the significance threshold of a true association (especially in light of multiple-hypothesis testing aggravated by publication bias for positive associations), how best to analyze a given dataset, and what constitutes a valid refutation. The editors suggested that they would expect manuscripts reporting genetic associations to include an estimate of the effect size and to contain either a replication in an independent sample or physiologically meaningful data supporting a functional role of the polymorphism in question. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10319853+10319855+10319854+9697696" 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="#27" class="mim-tip-reference" title="Saunders, A. J., Bertram, L., Mullin, K., Sampson, A. J., Latifzai, K., Basu, S., Jones, J., Kinney, D., MacKenzie-Ingano, L., Yu, S., Albert, M. S., Moscarillo, T. J., and 10 others. <strong>Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin.</strong> Hum. Molec. Genet. 12: 2765-2776, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966032</a>] [<a href="https://doi.org/10.1093/hmg/ddg310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966032">Saunders et al. (2003)</a> resequenced the A2M locus and identified 7 novel polymorphisms to test for genetic association with AD. Using the full NIMH sample of 1,439 individuals in 437 families, they found significant genetic association of the 5-bp deletion (<a href="#0005">103950.0005</a>) and 2 novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remained significantly associated with AD even after correction for multiple testing. The data supported a potential role for A2M or a nearby gene in AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966032" 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="Bian, L., Yang, J. D., Guo, T. W., Duan, Y., Qin, W., Sun, Y., Feng, G. Y., He, L. <strong>Association study of the A2M and LRP1 genes with Alzheimer disease in the Han Chinese.</strong> Biol. Psychiat. 58: 731-737, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16040006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16040006</a>] [<a href="https://doi.org/10.1016/j.biopsych.2005.05.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16040006">Bian et al. (2005)</a> found no association of 6 A2M gene polymorphisms (5-prime UTR A/G, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs226379;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs226379</a>; T/G, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs226380;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs226380</a>, intron 6 A/C; exon 24 A/G; intron 27 A/G; intron 34 T/C, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3759277;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3759277</a>) with AD in a study of 216 late-onset AD patients and 200 control subjects from the Han Chinese population. Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16040006" 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="Flachsbart, F., Caliebe, A., Nothnagel, M., Kleindorp, R., Nikolaus, S., Schreiber, S., Nebel, A. <strong>Depletion of potential A2M risk haplotype for Alzheimer's disease in long-lived individuals.</strong> Europ. J. Hum. Genet. 18: 59-61, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19639019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19639019</a>] [<a href="https://doi.org/10.1038/ejhg.2009.136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19639019">Flachsbart et al. (2010)</a> found that an A2M risk haplotype for Alzheimer disease, comprising <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3832852;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3832852</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs669;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs669</a>, was significantly less frequent among 1,042 long-lived German individuals, aged 95 to 100 years, without AD compared to 1,040 younger German individuals, aged 60 to 75 years, without AD. The results suggested that the haplotype is a mortality factor in the elderly. The findings were independent of APOE status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19639019" 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>From comparison of the sequence of the subunit of human alpha-2-macroglobulin with those of C3 (<a href="/entry/120700">120700</a>) and C4 (<a href="/entry/120810">120810</a>, <a href="/entry/120820">120820</a>), <a href="#28" class="mim-tip-reference" title="Sottrup-Jensen, L., Stepanik, T. M., Kristensen, T., Lonblad, P. B., Jones, C. M., Wierzbicki, D. M., Magnusson, S., Domdey, H., Wetsel, R. A., Lundwall, A., Tack, B. F., Fey, G. H. <strong>Common evolutionary origin of alpha-2-macroglobulin and complement components C3 and C4.</strong> Proc. Nat. Acad. Sci. 82: 9-13, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2578664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2578664</a>] [<a href="https://doi.org/10.1073/pnas.82.1.9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2578664">Sottrup-Jensen et al. (1985)</a> concluded that these 3 proteins, which all contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary origin. C5 (<a href="/entry/120900">120900</a>) also shows sequence homology to A2M. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2578664" 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="#30" class="mim-tip-reference" title="Umans, L., Serneels, L., Overbergh, L., Lorent, K., Van Leuven, F., Van den Berghe, H. <strong>Targeted inactivation of the mouse alpha-2-macroglobulin gene.</strong> J. Biol. Chem. 270: 19778-19785, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544347</a>] [<a href="https://doi.org/10.1074/jbc.270.34.19778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544347">Umans et al. (1995)</a> created mice lacking the alpha-2-macroglobulin gene. The knockout mice were not only viable, but more resistant to endotoxin. They produced normal-sized litters and showed no obvious phenotypic abnormalities. <a href="#31" class="mim-tip-reference" title="Webb, D. J., Wen, J., Lysiak, J. J., Umans, L., Van Leuven, F., Gonias, S. L. <strong>Murine alpha-macroglobulins demonstrate divergent activities as neutralizers of transforming growth factor-beta and as inducers of nitric oxide synthesis: a possible mechanism for the endotoxin insensitivity of the alpha-2-macroglobulin gene knock-out mouse.</strong> J. Biol. Chem. 271: 24982-24988, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8798779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8798779</a>] [<a href="https://doi.org/10.1074/jbc.271.40.24982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8798779">Webb et al. (1996)</a> demonstrated that murine alpha-2-macroglobulin binds TGF-beta and inhibits TGF-beta-receptor interactions. They suggested that these results explain the endotoxin-insensitive phenotype of the knockout mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8798779+7544347" 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="#15" class="mim-tip-reference" title="Leikola, J., Fudenberg, H. H., Kasukawa, R., Milgrom, F. <strong>A new genetic polymorphism of human serum: alpha(2) macroglobulin (AL-M).</strong> Am. J. Hum. Genet. 24: 134-144, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4622731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4622731</a>]" pmid="4622731">Leikola et al. (1972)</a> identified an antigenic material of a high molecular weight that they termed alpha-2-macroglobulin. They detected a polymorphism in Japanese persons that was distinct from the Gm locus, which determines the serologic type of gamma immunoglobulin (see <a href="/entry/147100">147100</a>), the Am locus, which determines the serologic type of alpha immunoglobulin (see <a href="/entry/146900">146900</a> and <a href="/entry/147000">147000</a>), and haptoglobins (<a href="/entry/140100">140100</a>). It was likewise distinct from Xm (<a href="/entry/314900">314900</a>), also a macroglobulin, as indicated by the autosomal inheritance and specific tests. Gene frequency of the allele whose product was demonstrated by the antiserum was about 0.16 in Japanese. Using a rabbit antihuman serum, <a href="#12" class="mim-tip-reference" title="Gallango, M. L., Castillo, O. <strong>Alpha-2-macroglobulin polymorphism: a new genetic system detected by immuno-electrophoresis.</strong> J. Immunogenet. 1: 147-151, 1974."None>Gallango and Castillo (1974)</a> also described a polymorphism of alpha-2-macroglobulin. This may be separate from that described by <a href="#15" class="mim-tip-reference" title="Leikola, J., Fudenberg, H. H., Kasukawa, R., Milgrom, F. <strong>A new genetic polymorphism of human serum: alpha(2) macroglobulin (AL-M).</strong> Am. J. Hum. Genet. 24: 134-144, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4622731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4622731</a>]" pmid="4622731">Leikola et al. (1972)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4622731" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>6 Selected Examples</a>):</strong>
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<a href="/allelicVariants/103950" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=103950[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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<strong>.0001 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs669;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/rs669?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs669" 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=rs669" 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=RCV000019801 OR RCV001618215" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019801, RCV001618215" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019801...</a>
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<p>By direct genomic sequencing of the 2 exons encoding the bait region and the exon encoding the thiolester site in 30 healthy individuals and in 30 patients with chronic lung disease, <a href="#24" class="mim-tip-reference" title="Poller, W., Faber, J.-P., Klobeck, G., Olek, K. <strong>Cloning of the human alpha-2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site.</strong> Hum. Genet. 88: 313-319, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370808</a>] [<a href="https://doi.org/10.1007/BF00197266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1370808">Poller et al. (1992)</a> found a sequence polymorphism near the thiolester site of the gene, changing val1000 (GTC) to ile (ATC); the 2 alleles had frequencies of 0.30 and 0.70, respectively. No difference of A2M serum levels was observed for these 2 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1370808" 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 proteinase inhibitor alpha-2-macroglobulin is found in association with senile plaques in Alzheimer disease (AD; <a href="/entry/104300">104300</a>). A2M has been implicated biochemically in binding and degradation of the amyloid beta protein which accumulates in senile plaques. In an initial exploratory dataset (90 controls and 171 AD cases), <a href="#16" class="mim-tip-reference" title="Liao, A., Nitsch, R. M., Greenberg, S. M., Finckh, U., Blacker, D., Albert, M., Rebeck, G. W., Gomez-Isla, T., Clatworthy, A., Binetti, G., Hock, C., Mueller-Thomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J. H., Tanzi, R. E., Hyman, B. T. <strong>Genetic association of an alpha-2-macroglobulin (val1000ile) polymorphism and Alzheimer's disease.</strong> Hum. Molec. Genet. 7: 1953-1956, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811940</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811940">Liao et al. (1998)</a> noted an increased frequency of the G/G genotype from 0.07 in controls to 0.12 in AD. An additional independent dataset of 359 controls and 566 AD patients were studied. In this hypothesis testing cohort, the G/G genotype again increased from 0.07 in controls to 0.12 in AD. The odds ratio for AD associated with the G/G genotype was 1.77 and in combination with APOE4 (see <a href="/entry/107741">107741</a>) was 9.68. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811940" 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 study of 148 patients from southern Italy with sporadic Alzheimer disease, <a href="#32" class="mim-tip-reference" title="Zappia, M., Manna, I., Serra, P., Cittadella, R., Andreoli, V., La Russa, A., Annesi, F., Spadafora, P., Romeo, N., Nicoletti, G., Messina, D., Gambardella, A., Quattrone, A. <strong>Increased risk for Alzheimer disease with the interaction of MPO and A2M polymorphisms.</strong> Arch. Neurol. 61: 341-344, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15023809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15023809</a>] [<a href="https://doi.org/10.1001/archneur.61.3.341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15023809">Zappia et al. (2004)</a> found an increase in the val/val genotype compared to controls, conferring an odds ratio of 3.58 for development of the disease. In combination with a myeloperoxidase promoter polymorphism genotype, -463G/G (<a href="/entry/606989#0008">606989.0008</a>), the odds ratio increased to 23.19. The authors suggested that the synergistic effect of the 2 genotypes may represent a facilitation of beta-amyloid deposition or a decrease in amyloid clearance. The findings were independent of APOE4 status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15023809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1800433 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800433;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=rs1800433" 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=rs1800433" 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=RCV000019803" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019803" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019803</a>
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<p>In 1 of 30 patients with chronic lung disease and in none of the 30 healthy persons studied by <a href="#24" class="mim-tip-reference" title="Poller, W., Faber, J.-P., Klobeck, G., Olek, K. <strong>Cloning of the human alpha-2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site.</strong> Hum. Genet. 88: 313-319, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370808</a>] [<a href="https://doi.org/10.1007/BF00197266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1370808">Poller et al. (1992)</a>, a mutation within the thiolester site, changing cys972 (TGT) to tyr (TAT), was found. Since activation of the internal thiolester formed between cys972 and gln975 in each of the subunits of the tetrameric A2M molecule is involved in the covalent crosslinking of the activating proteinase, this mutation was predicted to interfere with A2M function. The A2M serum level was within the normal range in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1370808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019804</a>
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<p>In 1 healthy individual, <a href="#24" class="mim-tip-reference" title="Poller, W., Faber, J.-P., Klobeck, G., Olek, K. <strong>Cloning of the human alpha-2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site.</strong> Hum. Genet. 88: 313-319, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370808</a>] [<a href="https://doi.org/10.1007/BF00197266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1370808">Poller et al. (1992)</a> found a deletion of the intron that ordinarily separates exons 1 and 2. As a result, the 2 exons that code the bait domain of the alpha-2-macroglobulin gene were fused. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1370808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800434;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/rs1800434?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800434" 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=rs1800434" 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=RCV000019805" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019805" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019805</a>
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<p><a href="#20" class="mim-tip-reference" title="Matthijs, G., Devriendt, K., Cassiman, J.-J., van den Berghe, H., Marynen, P. <strong>Structure of the human alpha-2 macroglobulin gene and its promotor (sic).</strong> Biochem. Biophys. Res. Commun. 184: 596-603, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1374237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1374237</a>] [<a href="https://doi.org/10.1016/0006-291x(92)90631-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1374237">Matthijs et al. (1992)</a> demonstrated an amino acid polymorphism in the bait domain of the alpha-2-macroglobulin molecule which defines the specific interaction of the molecule with proteinases. A G-to-A transition in exon 17 was detected in 1 person out of a group of 132 tested. The change predicted an arginine-to-his substitution at position 681. In the mutant allele an MaeII restriction site was lost and a new NspHI site was created. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1374237" 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 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019807 OR RCV000454529 OR RCV001724005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019807, RCV000454529, RCV001724005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019807...</a>
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<p><a href="#21" class="mim-tip-reference" title="Matthijs, G., Marynen, P. <strong>A deletion polymorphism in the human alpha-2-macroglobulin (A2M) gene.</strong> Nucleic Acids Res. 19: 5102 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1717945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1717945</a>] [<a href="https://doi.org/10.1093/nar/19.18.5102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1717945">Matthijs and Marynen (1991)</a> described a deletion polymorphism of the A2M gene, a 5-prime splice site deletion in exon 18. This exon encodes 'exon II' of the bait domain of alpha-2-microglobulin, which functions to attract and trap proteases. <a href="#6" class="mim-tip-reference" title="Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E. <strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong> Nature Genet. 19: 357-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>] [<a href="https://doi.org/10.1038/1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697696">Blacker et al. (1998)</a> found that this deletion, referred to as A2M-2, conferred increased risk for Alzheimer disease (<a href="/entry/104300">104300</a>). The possibility increased risk for AD but without modifying age of onset. It is possible that association of A2M-2 with AD reflected linkage disequilibrium with another mutation in A2M or a nearby gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1717945+9697696" 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 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1799759 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1799759;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=rs1799759" 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=rs1799759" 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=RCV000019807 OR RCV000454529 OR RCV001724005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019807, RCV000454529, RCV001724005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019807...</a>
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<p><a href="#21" class="mim-tip-reference" title="Matthijs, G., Marynen, P. <strong>A deletion polymorphism in the human alpha-2-macroglobulin (A2M) gene.</strong> Nucleic Acids Res. 19: 5102 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1717945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1717945</a>] [<a href="https://doi.org/10.1093/nar/19.18.5102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1717945">Matthijs and Marynen (1991)</a> described a deletion polymorphism of the A2M gene: 5 bases from -7 to -3 from the 5-prime splice site of exon 2. Codominant segregation of the polymorphism was shown in 2 informative families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1717945" 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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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<div id="mimSeeAlsoFold" class="collapse in mimTextToggleFold">
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<a href="#Bell1985" class="mim-tip-reference" title="Bell, G. I., Rall, L. B., Sanchez-Pescador, R., Merryweather, J. P., Scott, J., Eddy, R. L., Shows, T. B. <strong>Human alpha-2-macroglobulin gene is located on chromosome 12.</strong> Somat. Cell Molec. Genet. 11: 285-289, 1985.">Bell et al. (1985)</a>; <a href="#David1987" class="mim-tip-reference" title="David, F., Kan, C. C., Lucotte, G. <strong>Two Taq I RFLPs for human alpha-2 macroglobulin (alpha-2M) using a full length cDNA probe.</strong> Nucleic Acids Res. 15: 374 only, 1987.">David et al. (1987)</a>; <a href="#Marynen1985" class="mim-tip-reference" title="Marynen, P., Bell, G. I., Cavalli-Sforza, L. L. <strong>Three RFLPs associated with the human alpha-2-macroglobulin gene (A2M).</strong> Nucleic Acids Res. 13: 8287 only, 1985.">Marynen et al. (1985)</a>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Anonymous1999" class="mim-anchor"></a>
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Anonymous.
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<strong>Freely associating. (Editorial)</strong>
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Nature Genet. 22: 1-2, 1999.
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<a id="Bell1985" class="mim-anchor"></a>
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Bell, G. I., Rall, L. B., Sanchez-Pescador, R., Merryweather, J. P., Scott, J., Eddy, R. L., Shows, T. B.
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<strong>Human alpha-2-macroglobulin gene is located on chromosome 12.</strong>
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Somat. Cell Molec. Genet. 11: 285-289, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2408344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2408344</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2408344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01534685" target="_blank">Full Text</a>]
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<a id="Bergqvist1979" class="mim-anchor"></a>
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Bergqvist, D., Nilsson, I. M.
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<strong>Hereditary alpha-2-macroglobulin deficiency.</strong>
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Scand. J. Haemat. 23: 433-436, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/94459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">94459</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=94459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Bian2005" class="mim-anchor"></a>
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Bian, L., Yang, J. D., Guo, T. W., Duan, Y., Qin, W., Sun, Y., Feng, G. Y., He, L.
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<strong>Association study of the A2M and LRP1 genes with Alzheimer disease in the Han Chinese.</strong>
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Biol. Psychiat. 58: 731-737, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16040006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16040006</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16040006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.biopsych.2005.05.013" target="_blank">Full Text</a>]
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<a id="Blacker1999" class="mim-anchor"></a>
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Blacker, D., Crystal, A. S., Wilcox, M. A., Laird, N. M., Tanzi, R. E.
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<strong>Reply to Rudrasingham et al. (Letter)</strong>
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Nature Genet. 22: 21-22, 1999.
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<a id="Blacker1998" class="mim-anchor"></a>
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Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E.
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<strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong>
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Nature Genet. 19: 357-360, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9697696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/1243" target="_blank">Full Text</a>]
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<a id="David1987" class="mim-anchor"></a>
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David, F., Kan, C. C., Lucotte, G.
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<strong>Two Taq I RFLPs for human alpha-2 macroglobulin (alpha-2M) using a full length cDNA probe.</strong>
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Nucleic Acids Res. 15: 374 only, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2434923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2434923</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2434923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/nar/15.1.374" target="_blank">Full Text</a>]
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<a id="Devriendt1989" class="mim-anchor"></a>
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Devriendt, K., Zhang, J., van Leuven, F., van den Berghe, H., Cassiman, J. J., Marynen, P.
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<strong>A cluster of alpha 2-macroglobulin-related genes (alpha 2 M) on human chromosome 12p: cloning of the pregnancy-zone protein gene and an alpha 2M pseudogene.</strong>
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Gene 81: 325-334, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2478422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2478422</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2478422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0378-1119(89)90193-5" target="_blank">Full Text</a>]
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<a id="Dow1999" class="mim-anchor"></a>
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Dow, D. J., Lindsey, N., Cairns, N. J., Brayne, C., Robinson, D., Huppert, F. A., Paykel, E. S., Xuereb, J., Wilcock, G., Whittaker, J. L., Rubinsztein, D. C.
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<strong>Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK. (Letter)</strong>
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Nature Genet. 22: 16-17, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319853</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10319853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/8724" target="_blank">Full Text</a>]
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<a id="Flachsbart2010" class="mim-anchor"></a>
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Flachsbart, F., Caliebe, A., Nothnagel, M., Kleindorp, R., Nikolaus, S., Schreiber, S., Nebel, A.
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<strong>Depletion of potential A2M risk haplotype for Alzheimer's disease in long-lived individuals.</strong>
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Europ. J. Hum. Genet. 18: 59-61, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19639019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19639019</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19639019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.136" target="_blank">Full Text</a>]
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<a id="Fukushima1988" class="mim-anchor"></a>
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Fukushima, Y., Bell, G. I., Shows, T. B.
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<strong>The polymorphic human alpha-2-macroglobulin gene (A2M) is located in chromosome region 12p12.3-p13.3.</strong>
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Cytogenet. Cell Genet. 48: 58-59, 1988.
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[<a href="https://doi.org/10.1159/000132587" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00356160" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.8.2282" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.12.1953" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M801762200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/13.22.8287" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(92)90631-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/19.18.5102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00274157" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00197266" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/8729" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/8726" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.1.9" target="_blank">Full Text</a>]
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<a id="Umans1994" class="mim-anchor"></a>
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<div class="">
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Umans, L., Serneels, L., Hilliker, C., Stas, L., Overbergh, L., De Strooper, B., Van Leuven, F., Van den Berghe, H.
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<strong>Molecular cloning of the mouse gene coding for alpha-2-macroglobulin and targeting of the gene in embryonic stem cells.</strong>
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Genomics 22: 519-529, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7528166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7528166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7528166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1425" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Umans1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Umans, L., Serneels, L., Overbergh, L., Lorent, K., Van Leuven, F., Van den Berghe, H.
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<strong>Targeted inactivation of the mouse alpha-2-macroglobulin gene.</strong>
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J. Biol. Chem. 270: 19778-19785, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7544347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.270.34.19778" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
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<a id="Webb1996" class="mim-anchor"></a>
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<p class="mim-text-font">
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Webb, D. J., Wen, J., Lysiak, J. J., Umans, L., Van Leuven, F., Gonias, S. L.
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<strong>Murine alpha-macroglobulins demonstrate divergent activities as neutralizers of transforming growth factor-beta and as inducers of nitric oxide synthesis: a possible mechanism for the endotoxin insensitivity of the alpha-2-macroglobulin gene knock-out mouse.</strong>
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J. Biol. Chem. 271: 24982-24988, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8798779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8798779</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8798779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.271.40.24982" target="_blank">Full Text</a>]
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</p>
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<a id="32" class="mim-anchor"></a>
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<a id="Zappia2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zappia, M., Manna, I., Serra, P., Cittadella, R., Andreoli, V., La Russa, A., Annesi, F., Spadafora, P., Romeo, N., Nicoletti, G., Messina, D., Gambardella, A., Quattrone, A.
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<strong>Increased risk for Alzheimer disease with the interaction of MPO and A2M polymorphisms.</strong>
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Arch. Neurol. 61: 341-344, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15023809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15023809</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15023809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneur.61.3.341" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 11/2/2010
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 3/9/2010<br>John Logan Black, III - updated : 7/12/2006<br>George E. Tiller - updated : 1/31/2006<br>Cassandra L. Kniffin - updated : 6/16/2004<br>Cassandra L. Kniffin - reorganized : 1/17/2003<br>Victor A. McKusick - updated : 7/28/1999<br>Victor A. McKusick - updated : 4/27/1999<br>Victor A. McKusick - updated : 11/10/1998<br>Victor A. McKusick - updated : 8/13/1998<br>Victor A. McKusick - updated : 7/28/1998<br>Lori M. Kelman - updated : 6/3/1997
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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carol : 01/10/2025
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<span class="mim-text-font">
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carol : 11/25/2024<br>carol : 06/23/2021<br>carol : 06/09/2011<br>alopez : 11/10/2010<br>mgross : 11/5/2010<br>terry : 11/2/2010<br>carol : 5/25/2010<br>wwang : 4/7/2010<br>ckniffin : 3/9/2010<br>ckniffin : 3/9/2010<br>carol : 7/12/2006<br>terry : 7/12/2006<br>wwang : 2/9/2006<br>terry : 1/31/2006<br>tkritzer : 7/2/2004<br>ckniffin : 6/22/2004<br>ckniffin : 6/16/2004<br>mgross : 3/17/2004<br>carol : 1/17/2003<br>ckniffin : 1/8/2003<br>tkritzer : 12/23/2002<br>ckniffin : 12/18/2002<br>ckniffin : 12/18/2002<br>joanna : 4/3/2001<br>carol : 7/28/1999<br>alopez : 4/29/1999<br>terry : 4/27/1999<br>carol : 11/13/1998<br>terry : 11/10/1998<br>carol : 8/17/1998<br>terry : 8/13/1998<br>alopez : 7/31/1998<br>terry : 7/28/1998<br>terry : 11/21/1997<br>alopez : 6/3/1997<br>alopez : 4/4/1997<br>alopez : 4/1/1997<br>alopez : 3/21/1997<br>carol : 9/12/1994<br>mimadm : 3/11/1994<br>carol : 1/15/1993<br>carol : 6/19/1992<br>supermim : 3/16/1992<br>carol : 2/29/1992
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<strong>*</strong> 103950
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<h3>
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ALPHA-2-MACROGLOBULIN; A2M
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<em>Alternative titles; symbols</em>
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MACROGLOBULIN, ALPHA-2
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<strong><em>HGNC Approved Gene Symbol: A2M</em></strong>
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<em>
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Cytogenetic location: 12p13.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:9,067,708-9,116,229 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>A2M is a 718-kD homotetrameric glycoprotein of plasma and extracellular spaces that was first recognized as a broad spectrum protease inhibitor. A2M is activated by proteases with which it interacts, and this proteolytic activation causes a conformational change that traps the protease within the A2M homotetramer. In addition, A2M contains several independent domains that function as carriers of specific growth factors and/or binding sites for receptors. Activation of A2M by proteases alters the interaction of A2M with these ligands and induces cell signaling (summary by Mantuano et al., 2008). </p>
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<strong>Cloning and Expression</strong>
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<p>Using synthetic oligonucleotides as hybridization probes, Kan et al. (1985) isolated A2M cDNA clones from a human liver cDNA library. The coding sequence predicted a 1,451-amino acid polypeptide. Human A2M is a tetramer of 4 identical 185-kD subunits arranged as a pair of dimers, each consisting of 2 disulfide-linked monomers. The protein has a bait region composed of peptide bonds for plasma proteases and a thiol ester bond which, when hydrolyzed, leads to covalent bonding between the protease and A2M. </p>
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<strong>Gene Structure</strong>
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<p>Matthijs et al. (1992) demonstrated that the A2M gene spans approximately 48 kb and has 36 exons, from 21 to 229 bp in size and with consensus splice sites. Intron sizes range from 125 bp to 7.5 kb. The A2M gene is present in single copy in the haploid genome. Umans et al. (1994) found that the homologous gene in the mouse contains 36 exons, coding for a 4.8-kb cDNA. Including putative control elements in the 5-prime flanking region, the gene covers about 45 kb. The promoter region of the mouse A2m gene differed considerably from the known promoter sequences of the human and rat genes. </p>
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<strong>Mapping</strong>
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<p>Kan et al. (1985) assigned the A2M locus to chromosome 12 by Southern blot analysis of DNA from a panel of mouse/human somatic cell hybrids, using A2M cDNA as a hybridization probe. Fukushima et al. (1988) assigned the A2M locus to 12p13.3-p12.3 by in situ hybridization. Assignment of the A2M gene to human chromosome 12p13-p12.2 was confirmed by Marynen et al. (1989) by use of in situ hybridization and somatic cell hybrid DNA analysis. Devriendt et al. (1989) also assigned A2M to 12p13-p12 by analysis of somatic cell hybrids and in situ hybridization. They showed, furthermore, that a closely related gene for pregnancy-zone protein (PZP; 176420) and an A2M pseudogene map to the same region. Hilliker et al. (1992) showed that the gene is located on mouse chromosome 6 band F1-G3 in a syntenic group that has its human counterpart on 12p13-p12. </p>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Alpha-2-macroglobulin is, like alpha-1-antitrypsin, alpha-2-antiplasmin, and antithrombin III, a protease inhibitor. It inhibits many proteases, including trypsin, thrombin, and collagenase (Bergqvist and Nilsson, 1979). </p><p>Mantuano et al. (2008) used isolated recombinant human A2M protein fragments, which they called FP3 and FP6, to characterize the cellular functions of specific A2M domains. FP3 contains residues 591 to 774 of A2M and includes the growth factor carrier sites, and FP6 contains residues 1242 to 1451 of A2M and includes the LRP1 (107770) recognition domain. FP6 rapidly and robustly activated Akt (see 164730) and Erk/MAP kinases (see 176948) in cultured rat Schwann cells and PC12 rat pheochromocytoma cells. FP6 also promoted neurite outgrowth and expression of Gap43 (162060). These cell signaling events were mediated by Lrp1 and depended on 2 lysines in FP6 that were required for Lrp1 binding. The ability of FP6 to trigger Lrp1-dependent cell signaling in PC12 cells was reproduced by a purified 18-kD fragment of human plasma A2M that included the LRP1 recognition domain. FP3 alone did not induce cell signaling in rat Schwann and PC12 cells, but it blocked Ngf-beta (NGFB; 162030)-induced activation of Akt and Erk/MAP kinases. FP3 did not block activation of cell signaling induced by FP6. </p><p>Using mass spectrometry, Peslova et al. (2009) showed that hepcidin (HAMP; 606464) in human plasma or serum was bound by albumin (ALB; 103600) and by A2M. Binding of hepcidin to albumin was nonspecific and displayed nonsaturable kinetics. However, binding of hepcidin to A2M was specific. Scatchard analysis estimated 2 hepcidin-binding sites per inactive A2M molecule. Proteolytic activation of A2M resulted in a sigmoidal binding curve, suggesting high-affinity cooperative allosteric binding of 4 hepcidin molecules per active A2M molecule. The hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased ferroportin (SLC40A1; 604653) expression in J774 murine macrophages more effectively than hepcidin alone. Peslova et al. (2009) hypothesized that A2M has a role in regulating hepcidin action by sequestration and subsequent release. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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---Alpha-2-Macroglobulin Deficiency</p><p>By the electroimmunoassay of Laurell, Bergqvist and Nilsson (1979) found alpha-2-macroglobulin deficiency (614036) in a 37-year-old man, his mother, and one daughter. The deficient persons were apparently heterozygotes. No clinical disadvantage resulted from the deficiency. </p><p>Poller et al. (1989) detected an alteration in the A2M gene in a patient with serum A2M deficiency and chronic lung disease since childhood. The alteration involved restriction sites detected with 10 different enzymes and was thought to have been caused by major deletion or rearrangement in the gene. Nine of the restriction enzymes used detected no polymorphism in 40 healthy control subjects and 39 patients with chronic obstructive pulmonary disease. The patient was heterozygous for the A2M alteration; Poller et al. (1989) suggested that this was responsible for the pulmonary disease. </p><p>---Alzheimer Disease</p><p>Alpha-2-macroglobulin has been implicated in Alzheimer disease (AD; see 104300) based on its ability to mediate the clearance and degradation of A-beta, the major component of amyloid beta deposits. Blacker et al. (1998) analyzed a deletion in the A2M gene (103950.0005) at the 5-prime splice site of 'exon II' of the bait region (exon 18) and found that inheritance of the deletion, designated A2M-2, conferred increased risk for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD. These values were comparable to those obtained for the APOE4 allele in the same sample, but in contrast to APOE4, A2M-2 did not affect age of onset. The observed association that A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which Blacker et al. (1998) were unable to confirm in their sample. Thus, A2M, the A2M receptor (LRP1; 107770), and the genes for 2 other LRP (low density lipoprotein-related protein) ligands, APOE (107741) and APP (104760), had all been genetically linked to AD, suggesting that these proteins may participate in the common neuropathogenic pathway leading to the disease. Liao et al. (1998) found an association between the val1000-to-ile polymorphism (103950.0001) and AD. </p><p>In a study of AD in 3 samples of patients in the U.K., Dow et al. (1999) failed to show a strong association between A2M-2 and AD risk. Rudrasingham et al. (1999) did not find associations between AD and A2M-2, or genotypes containing A2M-2, in a powerful, case-control sample. Using the same family-based association methods employed by Blacker et al. (1998), Rogaeva et al. (1999) also could not replicate the association of A2M-2 in 2 comparable, independent familial AD datasets or in a larger dataset of families from the same dataset tested by Blacker et al. (1998). Furthermore, they were unable to document any biologic effect of the A2M-2 allele on A2M RNA splicing, protein monomeric molecular mass, or protein levels in brain, liver, or plasma of A2M-2 carriers. Rogaeva et al. (1999) concluded that prior genetic evidence for an AD susceptibility locus on chromosome 12 likely arose from genetic variations other than in A2M-2 alleles. In a reply to these criticisms, Blacker et al. (1999) commented that they did not find it surprising that the case-control studies conducted by the groups of Rudrasingham et al. (1999), Rogaeva et al. (1999), and Dow et al. (1999) could not find an association. They suggested that the findings highlighted differences between family-based and case-control association studies. In an accompanying editorial (Anonymous, 1999), the editor of Nature Genetics pointed out the difficulties in evaluating the results of association studies. Unresolved fundamental issues included such matters as the significance threshold of a true association (especially in light of multiple-hypothesis testing aggravated by publication bias for positive associations), how best to analyze a given dataset, and what constitutes a valid refutation. The editors suggested that they would expect manuscripts reporting genetic associations to include an estimate of the effect size and to contain either a replication in an independent sample or physiologically meaningful data supporting a functional role of the polymorphism in question. </p><p>Saunders et al. (2003) resequenced the A2M locus and identified 7 novel polymorphisms to test for genetic association with AD. Using the full NIMH sample of 1,439 individuals in 437 families, they found significant genetic association of the 5-bp deletion (103950.0005) and 2 novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remained significantly associated with AD even after correction for multiple testing. The data supported a potential role for A2M or a nearby gene in AD. </p><p>Bian et al. (2005) found no association of 6 A2M gene polymorphisms (5-prime UTR A/G, rs226379; T/G, rs226380, intron 6 A/C; exon 24 A/G; intron 27 A/G; intron 34 T/C, rs3759277) with AD in a study of 216 late-onset AD patients and 200 control subjects from the Han Chinese population. Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects. </p><p>Flachsbart et al. (2010) found that an A2M risk haplotype for Alzheimer disease, comprising rs3832852 and rs669, was significantly less frequent among 1,042 long-lived German individuals, aged 95 to 100 years, without AD compared to 1,040 younger German individuals, aged 60 to 75 years, without AD. The results suggested that the haplotype is a mortality factor in the elderly. The findings were independent of APOE status. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>From comparison of the sequence of the subunit of human alpha-2-macroglobulin with those of C3 (120700) and C4 (120810, 120820), Sottrup-Jensen et al. (1985) concluded that these 3 proteins, which all contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary origin. C5 (120900) also shows sequence homology to A2M. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Umans et al. (1995) created mice lacking the alpha-2-macroglobulin gene. The knockout mice were not only viable, but more resistant to endotoxin. They produced normal-sized litters and showed no obvious phenotypic abnormalities. Webb et al. (1996) demonstrated that murine alpha-2-macroglobulin binds TGF-beta and inhibits TGF-beta-receptor interactions. They suggested that these results explain the endotoxin-insensitive phenotype of the knockout mice. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Leikola et al. (1972) identified an antigenic material of a high molecular weight that they termed alpha-2-macroglobulin. They detected a polymorphism in Japanese persons that was distinct from the Gm locus, which determines the serologic type of gamma immunoglobulin (see 147100), the Am locus, which determines the serologic type of alpha immunoglobulin (see 146900 and 147000), and haptoglobins (140100). It was likewise distinct from Xm (314900), also a macroglobulin, as indicated by the autosomal inheritance and specific tests. Gene frequency of the allele whose product was demonstrated by the antiserum was about 0.16 in Japanese. Using a rabbit antihuman serum, Gallango and Castillo (1974) also described a polymorphism of alpha-2-macroglobulin. This may be separate from that described by Leikola et al. (1972). </p>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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A2M, VAL1000ILE
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<br />
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SNP: rs669,
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gnomAD: rs669,
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ClinVar: RCV000019801, RCV001618215
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>By direct genomic sequencing of the 2 exons encoding the bait region and the exon encoding the thiolester site in 30 healthy individuals and in 30 patients with chronic lung disease, Poller et al. (1992) found a sequence polymorphism near the thiolester site of the gene, changing val1000 (GTC) to ile (ATC); the 2 alleles had frequencies of 0.30 and 0.70, respectively. No difference of A2M serum levels was observed for these 2 alleles. </p><p>The proteinase inhibitor alpha-2-macroglobulin is found in association with senile plaques in Alzheimer disease (AD; 104300). A2M has been implicated biochemically in binding and degradation of the amyloid beta protein which accumulates in senile plaques. In an initial exploratory dataset (90 controls and 171 AD cases), Liao et al. (1998) noted an increased frequency of the G/G genotype from 0.07 in controls to 0.12 in AD. An additional independent dataset of 359 controls and 566 AD patients were studied. In this hypothesis testing cohort, the G/G genotype again increased from 0.07 in controls to 0.12 in AD. The odds ratio for AD associated with the G/G genotype was 1.77 and in combination with APOE4 (see 107741) was 9.68. </p><p>In a study of 148 patients from southern Italy with sporadic Alzheimer disease, Zappia et al. (2004) found an increase in the val/val genotype compared to controls, conferring an odds ratio of 3.58 for development of the disease. In combination with a myeloperoxidase promoter polymorphism genotype, -463G/G (606989.0008), the odds ratio increased to 23.19. The authors suggested that the synergistic effect of the 2 genotypes may represent a facilitation of beta-amyloid deposition or a decrease in amyloid clearance. The findings were independent of APOE4 status. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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A2M, CYS972TYR
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<br />
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SNP: rs1800433,
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ClinVar: RCV000019803
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 of 30 patients with chronic lung disease and in none of the 30 healthy persons studied by Poller et al. (1992), a mutation within the thiolester site, changing cys972 (TGT) to tyr (TAT), was found. Since activation of the internal thiolester formed between cys972 and gln975 in each of the subunits of the tetrameric A2M molecule is involved in the covalent crosslinking of the activating proteinase, this mutation was predicted to interfere with A2M function. The A2M serum level was within the normal range in this patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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A2M, IVS1DEL
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<br />
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ClinVar: RCV000019804
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 healthy individual, Poller et al. (1992) found a deletion of the intron that ordinarily separates exons 1 and 2. As a result, the 2 exons that code the bait domain of the alpha-2-macroglobulin gene were fused. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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A2M, ARG681HIS
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<br />
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SNP: rs1800434,
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gnomAD: rs1800434,
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ClinVar: RCV000019805
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Matthijs et al. (1992) demonstrated an amino acid polymorphism in the bait domain of the alpha-2-macroglobulin molecule which defines the specific interaction of the molecule with proteinases. A G-to-A transition in exon 17 was detected in 1 person out of a group of 132 tested. The change predicted an arginine-to-his substitution at position 681. In the mutant allele an MaeII restriction site was lost and a new NspHI site was created. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
A2M, EX18DEL
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<br />
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ClinVar: RCV000019807, RCV000454529, RCV001724005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Matthijs and Marynen (1991) described a deletion polymorphism of the A2M gene, a 5-prime splice site deletion in exon 18. This exon encodes 'exon II' of the bait domain of alpha-2-microglobulin, which functions to attract and trap proteases. Blacker et al. (1998) found that this deletion, referred to as A2M-2, conferred increased risk for Alzheimer disease (104300). The possibility increased risk for AD but without modifying age of onset. It is possible that association of A2M-2 with AD reflected linkage disequilibrium with another mutation in A2M or a nearby gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 ALPHA-2-MACROGLOBULIN POLYMORPHISM</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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A2M, 5-BP DEL
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<br />
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|
SNP: rs1799759,
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ClinVar: RCV000019807, RCV000454529, RCV001724005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Matthijs and Marynen (1991) described a deletion polymorphism of the A2M gene: 5 bases from -7 to -3 from the 5-prime splice site of exon 2. Codominant segregation of the polymorphism was shown in 2 informative families. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Bell et al. (1985); David et al. (1987); Marynen et al. (1985)
|
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Anonymous.
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<strong>Freely associating. (Editorial)</strong>
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Nature Genet. 22: 1-2, 1999.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bell, G. I., Rall, L. B., Sanchez-Pescador, R., Merryweather, J. P., Scott, J., Eddy, R. L., Shows, T. B.
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|
<strong>Human alpha-2-macroglobulin gene is located on chromosome 12.</strong>
|
|
Somat. Cell Molec. Genet. 11: 285-289, 1985.
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[PubMed: 2408344]
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[Full Text: https://doi.org/10.1007/BF01534685]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bergqvist, D., Nilsson, I. M.
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<strong>Hereditary alpha-2-macroglobulin deficiency.</strong>
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Scand. J. Haemat. 23: 433-436, 1979.
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[PubMed: 94459]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bian, L., Yang, J. D., Guo, T. W., Duan, Y., Qin, W., Sun, Y., Feng, G. Y., He, L.
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<strong>Association study of the A2M and LRP1 genes with Alzheimer disease in the Han Chinese.</strong>
|
|
Biol. Psychiat. 58: 731-737, 2005.
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[PubMed: 16040006]
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[Full Text: https://doi.org/10.1016/j.biopsych.2005.05.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Blacker, D., Crystal, A. S., Wilcox, M. A., Laird, N. M., Tanzi, R. E.
|
|
<strong>Reply to Rudrasingham et al. (Letter)</strong>
|
|
Nature Genet. 22: 21-22, 1999.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C. P., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T., Tanzi, R. E.
|
|
<strong>Alpha-2 macroglobulin is genetically associated with Alzheimer disease.</strong>
|
|
Nature Genet. 19: 357-360, 1998.
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[PubMed: 9697696]
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[Full Text: https://doi.org/10.1038/1243]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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David, F., Kan, C. C., Lucotte, G.
|
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<strong>Two Taq I RFLPs for human alpha-2 macroglobulin (alpha-2M) using a full length cDNA probe.</strong>
|
|
Nucleic Acids Res. 15: 374 only, 1987.
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[PubMed: 2434923]
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[Full Text: https://doi.org/10.1093/nar/15.1.374]
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</p>
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</li>
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<li>
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<strong>Murine alpha-macroglobulins demonstrate divergent activities as neutralizers of transforming growth factor-beta and as inducers of nitric oxide synthesis: a possible mechanism for the endotoxin insensitivity of the alpha-2-macroglobulin gene knock-out mouse.</strong>
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Zappia, M., Manna, I., Serra, P., Cittadella, R., Andreoli, V., La Russa, A., Annesi, F., Spadafora, P., Romeo, N., Nicoletti, G., Messina, D., Gambardella, A., Quattrone, A.
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