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Entry
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- *607575 - ADENOSINE DEAMINASE 2; ADA2
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- OMIM
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<p>
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<span class="h4">*607575</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</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/607575">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<h4 class="panel-title">
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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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<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=ENSG00000093072;t=ENST00000399837" 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=51816" 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=607575" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000093072;t=ENST00000399837" 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_001282225,NM_001282226,NM_001282227,NM_001282228,NM_001282229,NM_177405,XM_011546133,XM_047441406,XM_047441407" 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_001282225" 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=607575" 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=10462&isoform_id=10462_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/ADA2" 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/7650202,14042544,22760316,29029552,30704990,47678365,62088876,119578154,119578155,122065151,158258815,189067259,194379664,194388364,532691754,532691757,532691759,532691761,532691763,768022807,2217339817,2217339819,2462585006,2462585008,2462585010" 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/Q9NZK5" 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 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=51816" 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=ENSG00000093072;t=ENST00000399837" 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=ADA2" 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=ADA2" 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+51816" 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/ADA2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:51816" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/51816" 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=chr22&hgg_gene=ENST00000399837.8&hgg_start=17178790&hgg_end=17221848&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1839" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1839" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ada2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607575[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607575[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/ADA2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000093072" 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=ADA2" 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=ADA2" 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=ADA2" 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=ADA2&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/PA26382" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1839" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0033952.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ADA2#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="https://www.ncbi.nlm.nih.gov/gene/51816/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=51816" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030902-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="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:51816" 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=ADA2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 238776001, 716745004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607575
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ADENOSINE DEAMINASE 2; ADA2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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CAT EYE SYNDROME CHROMOSOME REGION, CANDIDATE 1; CECR1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ADA2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ADA2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/22/10?start=-3&limit=10&highlight=10">22q11.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:17178790-17221848&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'})">22:17,178,790-17,221,848</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=182410,615688" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/22/10?start=-3&limit=10&highlight=10">
|
|
22q11.1
|
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</a>
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Sneddon syndrome
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<a href="/entry/182410"> 182410 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/615688"> 615688 </a>
|
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
|
</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607575" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607575" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<p>ADA2 is an adenosine deaminase (ADA; <a href="https://enzyme.expasy.org/EC/3.5.4.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.5.4.4</a>) that catalyzes the deamination of adenosine and 2-prime-deoxyadenosine to inosine and deoxyinosine, respectively. Through their enzymatic action, ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors (see <a href="/entry/102775">102775</a>). ADA2 shares highest sequence similarity with ADA-related growth factors, which are involved in tissue development (summary by <a href="#9" class="mim-tip-reference" title="Zavialov, A. V., Yu, X., Spillmann, D., Lauvau, G., Zavialov, A. V. <strong>Structural basis for the growth factor activity of human adenosine deaminase ADA2.</strong> J. Biol. Chem. 285: 12367-12377, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20147294[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.M109.083527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20147294">Zavialov et al., 2010</a>). ADA2 is a secreted homodimer highly expressed in plasma (summary by <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20147294+24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Lee, P. Y. <strong>Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2.</strong> Front. Pediat. 6: 282, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30406060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30406060</a>] [<a href="https://doi.org/10.3389/fped.2018.00282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30406060">Lee (2018)</a> reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency (<a href="/entry/615688">615688</a>), which include vasculopathy, skin manifestations, neuropathy, immunodeficiency, and hematologic defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30406060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By exon trapping and genomic sequence analysis, <a href="#5" class="mim-tip-reference" title="Riazi, M. A., Brinkman-Mills, P., Nguyen, T., Pan, H., Phan, S., Ying, F., Roe, B. A., Tochigi, J., Shimizu, Y., Minoshima, S., Shimizu, N., Buchwald, M., McDermid, H. E. <strong>The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome.</strong> Genomics 64: 277-285, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10756095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10756095</a>] [<a href="https://doi.org/10.1006/geno.1999.6099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10756095">Riazi et al. (2000)</a> identified CECR1. They cloned the full-length cDNA by 5-prime RACE of total RNA from a lung cell line. The deduced protein contains 511 amino acids and shows sequence similarity to insect and mollusk growth factors. The N terminus contains a secretory signal peptide and the C-terminal half shows significant similarity to adenosine deaminase (ADA; <a href="/entry/608958">608958</a>), particularly in the conserved catalytic domain. Northern blot analysis detected 1.0-, 3.5-, and 4.4-kb transcripts that were differentially expressed. Highest expression was in adult heart, lung, lymphoblasts, spleen, and placenta, as well as in fetal lung, liver, and kidney. Expression was weaker in adult pancreas, skeletal muscle, and liver, and faint in adult and fetal brain. In situ hybridization of a 35-day human embryo detected CECR1 mRNA in the outflow tract and atrium of the heart, the VII/VIII cranial nerve ganglion, the notochord, and the placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10756095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Zavialov, A. V., Yu, X., Spillmann, D., Lauvau, G., Zavialov, A. V. <strong>Structural basis for the growth factor activity of human adenosine deaminase ADA2.</strong> J. Biol. Chem. 285: 12367-12377, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20147294[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.M109.083527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20147294">Zavialov et al. (2010)</a> determined that the putative 511-amino acid ADA2 protein contains an N-terminal signal peptide, a central ADA domain that covers over 70% of the mature ADA2 sequence, and several sites for N-glycosylation. The ADA domain of ADA2 shares 18 to 21% amino acid identity with the ADA1 (ADA) protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147294" 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="#5" class="mim-tip-reference" title="Riazi, M. A., Brinkman-Mills, P., Nguyen, T., Pan, H., Phan, S., Ying, F., Roe, B. A., Tochigi, J., Shimizu, Y., Minoshima, S., Shimizu, N., Buchwald, M., McDermid, H. E. <strong>The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome.</strong> Genomics 64: 277-285, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10756095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10756095</a>] [<a href="https://doi.org/10.1006/geno.1999.6099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10756095">Riazi et al. (2000)</a> determined that CECR1 contains 9 exons and spans more than 28 kb, including a 2.2-kb 3-prime untranslated region that is rich in Alu and LINE repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10756095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#5" class="mim-tip-reference" title="Riazi, M. A., Brinkman-Mills, P., Nguyen, T., Pan, H., Phan, S., Ying, F., Roe, B. A., Tochigi, J., Shimizu, Y., Minoshima, S., Shimizu, N., Buchwald, M., McDermid, H. E. <strong>The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome.</strong> Genomics 64: 277-285, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10756095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10756095</a>] [<a href="https://doi.org/10.1006/geno.1999.6099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10756095">Riazi et al. (2000)</a> mapped the CECR1 gene within the cat eye syndrome (<a href="/entry/115470">115470</a>) critical region on chromosome 22q11.2. Southern blot analysis revealed that CECR1 is a single-copy gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10756095" 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="#8" class="mim-tip-reference" title="Zavialov, A. V., Engstrom, A. <strong>Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity.</strong> Biochem. J. 391: 51-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15926889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15926889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15926889[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/10.1042/BJ20050683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15926889">Zavialov and Engstrom (2005)</a> purified ADA2 from human plasma and from commercial IgG preparations. Mass spectrometric and database analyses revealed that ADA2 is identical to the CECR1 protein. In vitro, ADA2 showed a pH optimum of pH 6.8 and a Km of about 2.25 mM in the deamination of adenosine. Gel filtration analysis revealed that ADA2 formed homodimers with an apparent molecular mass of 110 kD. Monomers had an apparent molecular mass of 57 kD by SDS-PAGE. <a href="#8" class="mim-tip-reference" title="Zavialov, A. V., Engstrom, A. <strong>Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity.</strong> Biochem. J. 391: 51-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15926889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15926889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15926889[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/10.1042/BJ20050683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15926889">Zavialov and Engstrom (2005)</a> found that ADA2 bound heparin in addition to IgG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15926889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Crystal Structure</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Zavialov, A. V., Yu, X., Spillmann, D., Lauvau, G., Zavialov, A. V. <strong>Structural basis for the growth factor activity of human adenosine deaminase ADA2.</strong> J. Biol. Chem. 285: 12367-12377, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20147294[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.M109.083527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20147294">Zavialov et al. (2010)</a> solved the crystal structures of human ADA2 apoenzyme and ADA2 homodimers complexed with a transition state analog to 2.0- and 2.5-angstrom resolution, respectively. The overall structure of the catalytic domain and catalytic site of ADA2 appeared similar to that of ADA1, suggesting the same catalytic mechanism. In ADA2, his86, his88, his330, and asp415 coordinated a zinc ion within the active-site cavity. The substrate-binding site in ADA2 appeared significantly different than that of ADA1. In contrast to the large conformational change observed in the active site of ADA1 upon substrate binding, little conformational change occurred in ADA2 dimers following binding to the transition state analog. ADA2 also assumed novel folds that mediated dimerization and binding to cell surface receptors. The highly conserved residues cys111 and cys133 within the ADA2 catalytic region formed a disulfide bond. Mutation of cys111 to gly or reduction of this disulfide bond reduced ADA2 secretion, led to massive aggregation of the protein, and reduced its ability to bind glycosaminoglycan. Oligosaccharide chains located on 3 different faces of ADA2 were positioned to protect the molecule against proteolysis in the extracellular space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Vasculitis, Autoinflammation, Immunodeficiency, and Hematologic Defects Syndrome</em></strong></p><p>
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In 9 patients from 8 unrelated families with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> identified homozygous or compound heterozygous mutations in the CECR1 gene (see, e.g., <a href="#0001">607575.0001</a>-<a href="#0006">607575.0006</a>). All mutations except 1 were missense mutations. The initial mutations were found by whole-exome sequencing, and subsequent mutations were found by candidate gene sequencing. The disorder was characterized by onset of recurrent ischemic, and less frequently hemorrhagic, stroke affecting the small vessels of the brain and resulting in neurologic dysfunction. Patients also had recurrent fever and livedo racemosa. Brain and skin biopsies from patients showed evidence of endothelial damage associated with increased staining for IL1B (<a href="/entry/147720">147720</a>), TNFA (<a href="/entry/191160">191160</a>), and inducible nitric oxide synthase (NOS2A; <a href="/entry/163730">163730</a>). Immunologic assessment of the patients, including laboratory studies of cell function and cytokine production, showed only mild abnormalities, such as hypogammaglobulinemia and increased B-cell death and reduced B-cell differentiation compared to controls. Patients had significantly decreased ADA2 activity in plasma, and Western blot analysis showed reduced ADA2 protein levels in cell lysates, consistent with a loss of function. ADA2 activity and protein levels in carrier parents were about 50% of normal. ADA1 (<a href="/entry/608958">608958</a>)-specific activity was preserved. Morpholino knockout of a CECR1 ortholog (cecr1b) in zebrafish resulted in intracranial bleeding that could be rescued by wildtype human CECR1, but not by mutant CECR1. Knockout of cecr1b in myeloid cells resulted in neutropenia. Knockdown of CECR1 using short hairpin RNA (shRNA) in human myeloid cells caused marked impairment of macrophage differentiation and disruption of cocultured monolayers of human microvascular endothelial cells. These defects in monocyte/macrophage differentiation were also seen in patients. <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> suggested that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and that ADA2 deficiency may polarize macrophages and monocytes toward proinflammatory cells, resulting in inflammation, endothelial cell damage, and small vessel vasculopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" 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 19 patients of Georgian Jewish descent with autosomal recessive polyarteritis nodosa, <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a> identified a homozygous missense mutation in the CECR1 gene (G47R; <a href="#0006">607575.0006</a>). The mutation was found by exome sequencing. Affected members of a German family and a Turkish patient with a similar disorder were subsequently found to carry compound heterozygous missense CECR1 mutations (<a href="#0005">607575.0005</a>; <a href="#0007">607575.0007</a>-<a href="#0009">607575.0009</a>). ADA2 activity was significantly reduced in patient serum samples, and in vitro cellular expression studies showed low amounts of secreted mutant protein, consistent with a loss of function. There was considerable variability in the severity and age at onset, although most patients had onset of symptoms in the first decade. Patients had systemic involvement of the skin, nervous system, gastrointestinal tract, and kidneys. Features included stroke resulting in neurologic dysfunction, gastrointestinal pain, fever, elevated acute-phase proteins, myalgias, and livedo reticularis with an inflammatory vasculitis on biopsy. Some patients developed hypertension, aneurysms, or ischemic necrosis of the digits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Sneddon Syndrome</em></strong></p><p>
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In 3 Portuguese sibs with Sneddon syndrome (SNDNS; <a href="/entry/182410">182410</a>), previously reported by <a href="#3" class="mim-tip-reference" title="Mascarenhas, R., Santo, G., Goncalo, M., Ferro, M. A., Tellechea, O., Figueiredo, A. <strong>Familial Sneddon's syndrome.</strong> Europ. J. Derm. 13: 283-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12804991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12804991</a>]" pmid="12804991">Mascarenhas et al. (2003)</a>, <a href="#1" class="mim-tip-reference" title="Bras, J., Guerreiro, R., Santo, G. C. <strong>Mutant ADA2 in vasculopathies. (Letter)</strong> New Eng. J. Med. 371: 478-480, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25075847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25075847</a>] [<a href="https://doi.org/10.1056/NEJMc1405506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25075847">Bras et al. (2014)</a> identified compound heterozygous missense mutations in the CECR1 gene (T119A, <a href="#0010">607575.0010</a> and G142S, <a href="#0011">607575.0011</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. The patients developed livedo racemosa, leg ulcerations, and intermittent fevers during the second decade of life, and had ischemic and/or hemorrhagic strokes in early adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12804991+25075847" 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 34-year-old woman with SNDNS, <a href="#6" class="mim-tip-reference" title="Tull, T. J., Martin, B., Spencer, J., Sangle, S., Chua, S., McGrath, J. A., D'Cruz, D. P., McGibbon, D. H. <strong>Sneddon syndrome associated with two novel ADA2 gene mutations.</strong> Rheumatology 59: 1448-1450, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31652311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31652311</a>] [<a href="https://doi.org/10.1093/rheumatology/kez446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31652311">Tull et al. (2020)</a> identified compound heterozygosity for mutations in the ADA2 gene (<a href="#0012">607575.0012</a>, <a href="#0013">607575.0013</a>). One mutation was inherited from her mother and the other arose de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31652311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607575[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 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs376785840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376785840;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/rs376785840?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=rs376785840" 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=rs376785840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated girls of European ancestry with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene. Both patients carried a c.1358A-G transition in exon 9 of the CECR1 gene, resulting in a tyr453-to-cys (Y453C) substitution in a catalytic domain. The second mutation in 1 patient was a c.326C-A transversion in exon 3, resulting in an ala109-to-asp (A109D; <a href="#0002">607575.0002</a>) substitution in a catalytic domain, whereas the second mutation in the other patient was a c.140G-C transversion in exon 2, resulting in a gly47-to-ala (G47A; <a href="#0003">607575.0003</a>) substitution in the dimerization domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Candidate gene sequencing of additional patients with the disorder identified 1 who was compound heterozygous for Y453C and R169Q (<a href="#0005">607575.0005</a>). Haplotype analysis indicated a founder effect for the Y453C mutation. All mutations occurred at highly conserved residues. The Y453C mutation was found in less than 1% of alleles in the Exome Variant Server database; it was not present in the dbSNP, 1000 Genomes Project, or ClinSeq 801 databases. Two Portuguese brothers among 94 patients with late-onset small-vessel ischemic stroke who were part of the Exome Variant Server database were found to carry a heterozygous Y453C mutation. The A109D mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the ala109-to-asp (A109D) mutation in the CECR1 gene that was found in compound heterozygous state in patients with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>) by <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a>, see <a href="#0001">607575.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" 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> rs200930463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200930463;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/rs200930463?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=rs200930463" 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=rs200930463" 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=RCV000106382 OR RCV001570811 OR RCV002483175 OR RCV004751262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106382, RCV001570811, RCV002483175, RCV004751262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106382...</a>
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<p>In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene: a c.140G-C transversion in exon 2, resulting in a gly47-to-ala (G47A) substitution in the dimerization domain, and a c.336C-G transversion in exon 3, resulting in a his112-to-gln (H112Q; <a href="#0004">607575.0004</a>) substitution in a catalytic domain. Another patient with the disorder was compound heterozygous for G47A and Y453C (<a href="#0001">607575.0001</a>). Both mutations occurred at highly conserved residues. Haplotype analysis indicated a founder effect for the G47A mutation. The G47A variant was found in less than 1% of alleles in the 1000 Genomes Project and ClinSeq 801 databases; it was not present in the Exome Variant Server database. The H112Q mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs587777241 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777241;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/rs587777241?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=rs587777241" 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=rs587777241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the his112-to-gln (H112Q) mutation in the CECR1 gene that was found in compound heterozygous state in a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>) by <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a>, see <a href="#0003">607575.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" 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 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs77563738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77563738;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/rs77563738?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=rs77563738" 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=rs77563738" 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=RCV000106384 OR RCV001027542 OR RCV001091904 OR RCV001536077 OR RCV001808328 OR RCV002262704 OR RCV003945041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106384, RCV001027542, RCV001091904, RCV001536077, RCV001808328, RCV002262704, RCV003945041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106384...</a>
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<p>In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene: a c.506G-A transition in exon 3, resulting in an arg169-to-gln (R169Q) substitution in the PRB domain, and Y453C (<a href="#0001">607575.0001</a>). Another patient with the disorder was compound heterozygous for R169Q and an intragenic 28-kb deletion. Both mutations occurred at highly conserved residues. Haplotype analysis indicated a founder effect for the R169Q mutation. The R169Q mutation was present in less than 1% of alleles in the 1000 Genomes Project and Exome Variant Server databases; it was not present in the ClinSeq 801 database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 German sibs with polyarteritis nodosa, <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene: R169Q and a c.752C-T transition, resulting in a pro251-to-leu (P251L; <a href="#0007">607575.0007</a>) substitution at a highly conserved residue. Each unaffected parent was heterozygous for 1 of the mutations. Among 4,300 European controls, the R169Q variant was found in 7 (0.0008) and the P251L variant was found in 1 (0.0001). Serum ADA2 activity in patients was severely reduced compared to controls. The R169Q protein was barely detectable in transfected cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="van Montfrans, J. M., Hartman, E. A. R., Braun, K. P. J., Hennekam, E. A. M., Hak, E. A., Nederkoorn, P. J., Westendorp, W. F., Bredius, R. G. M., Kollen, W. J. W., Scholvinck, E. H., Legger, G. E., Meyts, I. <strong>Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.</strong> Rheumatology 55: 902-910, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26867732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26867732</a>] [<a href="https://doi.org/10.1093/rheumatology/kev439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26867732">Van Montfrans et al. (2016)</a> identified a homozygous R169Q mutation in the ADA2 gene in 9 patients from 6 unrelated families from the Netherlands with highly variable presentations and manifestations. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26867732" 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 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs202134424 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs202134424;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/rs202134424?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=rs202134424" 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=rs202134424" 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=RCV000106385 OR RCV001091906 OR RCV002262705 OR RCV002498474 OR RCV003445509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106385, RCV001091906, RCV002262705, RCV002498474, RCV003445509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106385...</a>
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<p>In 3 Turkish patients, including 2 sibs, with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#10" class="mim-tip-reference" title="Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others. <strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong> New Eng. J. Med. 370: 911-920, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[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/10.1056/NEJMoa1307361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552284">Zhou et al. (2014)</a> identified a homozygous c.139G-A transition in exon 2 of the CECR1 gene, resulting in a gly47-to-arg (G47R) substitution at a highly conserved residue in the dimerization domain. Haplotype analysis indicated a founder effect, and the carrier frequency of this variant in Turkish controls was 0.002. The G47R mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" 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="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a> identified a homozygous G47R mutation in 19 Georgian Jewish individuals with polyarteritis nodosa. Sixteen of the patients were from 5 multiplex families, and 3 patients had apparently sporadic disease. Fifteen of the patients were diagnosed before 10 years of age, including 6 in infancy. In contrast, 1 patient had onset of the disorder with leg ulcers at age 59 years. The mutation, which was found by exome sequencing in the initial patients and later found and confirmed by Sanger sequencing in the other patients, was not present in 864 in-house exomes or in more than 7,500 exome sequences present in public databases. Among 246 unrelated Georgian Jewish controls, 25 were heterozygous for the mutation, yielding a carrier frequency of 0.102 in this population. Serum ADA2 activity in homozygous mutation carriers was reduced by a factor of more than 4 compared to controls. Transfection of the mutation into Drosophila cells resulted in decreased expression of the mutant protein compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs148936893 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148936893;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/rs148936893?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=rs148936893" 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=rs148936893" 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=RCV000106386 OR RCV001781437 OR RCV005025173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106386, RCV001781437, RCV005025173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106386...</a>
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<p>For discussion of the pro251-to-leu (P251L) mutation in the CECR1 gene that was found in compound heterozygous state in patients with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>) by <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a>, see <a href="#0005">607575.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<strong>.0008 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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> rs200930463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200930463;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/rs200930463?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=rs200930463" 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=rs200930463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000106387 OR RCV000481270 OR RCV002505023" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106387, RCV000481270, RCV002505023" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106387...</a>
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<p>In a Turkish man with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>), <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene: a c.140G-T transversion, resulting in a gly47-to-val (G47V) substitution, and a c.791G-C transversion, resulting in a trp264-to-ser (W264S; <a href="#0009">607575.0009</a>) substitution. Both mutations occurred at highly conserved residues. Each unaffected parent was heterozygous for 1 of the mutations, and neither mutation was found in 200 Turkish controls or in more than 7,500 exome sequences present in public databases. The mutant G47V protein was barely detectable in transfected cells, and the W264S mutant protein was retained intracellularly, resulting in decreased secretion of ADA2 into the media. Transfection of the G47V mutation into Drosophila cells resulted in decreased expression of the mutant protein; the W264S mutation caused decreased stability of the mutant protein compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
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</h4>
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ADA2, TRP264SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777242 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777242;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=rs587777242" 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=rs587777242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000106388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000106388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000106388</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>For discussion of the trp264-to-ser (W264S) mutation in the CECR1 gene that was found in compound heterozygous state in a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; <a href="/entry/615688">615688</a>) by <a href="#4" class="mim-tip-reference" title="Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others. <strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong> New Eng. J. Med. 370: 921-931, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>] [<a href="https://doi.org/10.1056/NEJMoa1307362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24552285">Navon Elkan et al. (2014)</a>, see <a href="#0008">607575.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 SNEDDON SYNDROME</strong>
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ADA2, THR119ALA
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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> rs775440641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs775440641;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/rs775440641?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=rs775440641" 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=rs775440641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000169758 OR RCV000851530 OR RCV004584361" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169758, RCV000851530, RCV004584361" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169758...</a>
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<p>In 3 Portuguese sibs with Sneddon syndrome (SNDNS; <a href="/entry/182410">182410</a>), previously reported by <a href="#3" class="mim-tip-reference" title="Mascarenhas, R., Santo, G., Goncalo, M., Ferro, M. A., Tellechea, O., Figueiredo, A. <strong>Familial Sneddon's syndrome.</strong> Europ. J. Derm. 13: 283-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12804991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12804991</a>]" pmid="12804991">Mascarenhas et al. (2003)</a>, <a href="#1" class="mim-tip-reference" title="Bras, J., Guerreiro, R., Santo, G. C. <strong>Mutant ADA2 in vasculopathies. (Letter)</strong> New Eng. J. Med. 371: 478-480, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25075847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25075847</a>] [<a href="https://doi.org/10.1056/NEJMc1405506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25075847">Bras et al. (2014)</a> identified compound heterozygous mutations in the CECR1 gene: a c.355A-G transition, resulting in a thr119-to-ala (T119A) substitution, and a c.424G-A transition, resulting in a gly142-to-ser (G142S; <a href="#0011">607575.0011</a>) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12804991+25075847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 SNEDDON SYNDROME</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> rs770689762 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770689762;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/rs770689762?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=rs770689762" 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=rs770689762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000169759 OR RCV001386673 OR RCV002460949 OR RCV002485053" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169759, RCV001386673, RCV002460949, RCV002485053" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169759...</a>
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<p>For discussion of the c.424G-A transition in the CECR1 gene, resulting in a gly142-to-ser (G142S) substitution, that was found in compound heterozygous state in patients with Sneddon syndrome (SNDNS; <a href="/entry/182410">182410</a>) by <a href="#1" class="mim-tip-reference" title="Bras, J., Guerreiro, R., Santo, G. C. <strong>Mutant ADA2 in vasculopathies. (Letter)</strong> New Eng. J. Med. 371: 478-480, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25075847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25075847</a>] [<a href="https://doi.org/10.1056/NEJMc1405506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25075847">Bras et al. (2014)</a>, see <a href="#0010">607575.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25075847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 SNEDDON SYNDROME</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">rs2123699776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2123699776;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=rs2123699776" 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=rs2123699776" 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=RCV001523887" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001523887" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001523887</a>
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<p>In a 34-year-old woman with Sneddon syndrome (SNDNS; <a href="/entry/182410">182410</a>), <a href="#6" class="mim-tip-reference" title="Tull, T. J., Martin, B., Spencer, J., Sangle, S., Chua, S., McGrath, J. A., D'Cruz, D. P., McGibbon, D. H. <strong>Sneddon syndrome associated with two novel ADA2 gene mutations.</strong> Rheumatology 59: 1448-1450, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31652311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31652311</a>] [<a href="https://doi.org/10.1093/rheumatology/kez446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31652311">Tull et al. (2020)</a> identified compound heterozygosity for mutations in the ADA2 gene: the first was a 3-bp in-frame deletion (c.634_636delTTC), resulting in deletion of the phe212 residue (F212del), and the second was a c.1225C-T transition resulting in a pro409-to-ser (P409S; <a href="#0013">607575.0013</a>) substitution. Her unaffected mother was heterozygous for the deletion, but no ADA2 mutations were detected in her father, indicating a de novo origin for the missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31652311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 SNEDDON SYNDROME</strong>
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ADA2, PRO409SER
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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> rs777618863 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777618863;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/rs777618863?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=rs777618863" 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=rs777618863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001523888 OR RCV001872009" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001523888, RCV001872009" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001523888...</a>
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<span class="mim-text-font">
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<p>For discussion of the c.1225C-T transition in the ADA2 gene, resulting in a pro409-to-ser (P409S) substitution, that was found in compound heterozygous state in a 34-year-old woman with Sneddon syndrome (SNDNS; <a href="/entry/182410">182410</a>) by <a href="#6" class="mim-tip-reference" title="Tull, T. J., Martin, B., Spencer, J., Sangle, S., Chua, S., McGrath, J. A., D'Cruz, D. P., McGibbon, D. H. <strong>Sneddon syndrome associated with two novel ADA2 gene mutations.</strong> Rheumatology 59: 1448-1450, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31652311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31652311</a>] [<a href="https://doi.org/10.1093/rheumatology/kez446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31652311">Tull et al. (2020)</a>, see <a href="#0012">607575.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31652311" 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="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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<a id="Bras2014" class="mim-anchor"></a>
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Bras, J., Guerreiro, R., Santo, G. C.
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<strong>Mutant ADA2 in vasculopathies. (Letter)</strong>
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[<a href="https://doi.org/10.1056/NEJMc1405506" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Lee2018" class="mim-anchor"></a>
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Lee, P. Y.
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<strong>Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2.</strong>
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Front. Pediat. 6: 282, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30406060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30406060</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30406060" 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/10.3389/fped.2018.00282" target="_blank">Full Text</a>]
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<a id="Mascarenhas2003" class="mim-anchor"></a>
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Mascarenhas, R., Santo, G., Goncalo, M., Ferro, M. A., Tellechea, O., Figueiredo, A.
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<strong>Familial Sneddon's syndrome.</strong>
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<a id="Navon Elkan2014" class="mim-anchor"></a>
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Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others.
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<strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552285</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552285" 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/10.1056/NEJMoa1307362" target="_blank">Full Text</a>]
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<a id="Riazi2000" class="mim-anchor"></a>
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Riazi, M. A., Brinkman-Mills, P., Nguyen, T., Pan, H., Phan, S., Ying, F., Roe, B. A., Tochigi, J., Shimizu, Y., Minoshima, S., Shimizu, N., Buchwald, M., McDermid, H. E.
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<strong>The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome.</strong>
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Genomics 64: 277-285, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10756095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10756095</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10756095" 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.1999.6099" target="_blank">Full Text</a>]
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<a id="Tull2020" class="mim-anchor"></a>
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Tull, T. J., Martin, B., Spencer, J., Sangle, S., Chua, S., McGrath, J. A., D'Cruz, D. P., McGibbon, D. H.
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<strong>Sneddon syndrome associated with two novel ADA2 gene mutations.</strong>
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Rheumatology 59: 1448-1450, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31652311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31652311</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31652311" 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/rheumatology/kez446" target="_blank">Full Text</a>]
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<a id="van Montfrans2016" class="mim-anchor"></a>
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van Montfrans, J. M., Hartman, E. A. R., Braun, K. P. J., Hennekam, E. A. M., Hak, E. A., Nederkoorn, P. J., Westendorp, W. F., Bredius, R. G. M., Kollen, W. J. W., Scholvinck, E. H., Legger, G. E., Meyts, I.
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<strong>Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.</strong>
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Rheumatology 55: 902-910, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26867732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26867732</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26867732" 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/rheumatology/kev439" target="_blank">Full Text</a>]
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Zavialov, A. V., Engstrom, A.
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<strong>Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15926889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15926889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15926889[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15926889" 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/10.1042/BJ20050683" target="_blank">Full Text</a>]
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Zavialov, A. V., Yu, X., Spillmann, D., Lauvau, G., Zavialov, A. V.
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<strong>Structural basis for the growth factor activity of human adenosine deaminase ADA2.</strong>
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J. Biol. Chem. 285: 12367-12377, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20147294[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147294" 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.M109.083527" target="_blank">Full Text</a>]
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<a id="Zhou2014" class="mim-anchor"></a>
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Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others.
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<strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong>
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New Eng. J. Med. 370: 911-920, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24552284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24552284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24552284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24552284" 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/10.1056/NEJMoa1307361" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Marla J. F. O'Neill - updated : 06/14/2021
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</span>
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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 : 04/03/2019<br>Cassandra L. Kniffin - updated : 8/4/2014<br>Cassandra L. Kniffin - updated : 3/11/2014<br>Patricia A. Hartz - updated : 12/14/2010
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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 : 2/24/2003
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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alopez : 06/16/2021
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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alopez : 06/14/2021<br>carol : 05/05/2021<br>carol : 04/04/2019<br>carol : 04/03/2019<br>ckniffin : 04/03/2019<br>mgross : 01/31/2019<br>carol : 03/28/2016<br>mcolton : 4/7/2015<br>carol : 8/6/2014<br>carol : 8/6/2014<br>mcolton : 8/6/2014<br>ckniffin : 8/4/2014<br>alopez : 3/26/2014<br>mcolton : 3/12/2014<br>ckniffin : 3/11/2014<br>mgross : 1/10/2011<br>terry : 12/14/2010<br>ckniffin : 10/28/2004<br>mgross : 2/24/2003
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607575
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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ADENOSINE DEAMINASE 2; ADA2
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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CAT EYE SYNDROME CHROMOSOME REGION, CANDIDATE 1; CECR1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ADA2</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 238776001, 716745004;
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<strong>
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<em>
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Cytogenetic location: 22q11.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:17,178,790-17,221,848 </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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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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22q11.1
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<td>
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<span class="mim-font">
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Sneddon syndrome
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</td>
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<td>
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<span class="mim-font">
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182410
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<span class="mim-font">
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Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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615688
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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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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<span class="mim-text-font">
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<p>ADA2 is an adenosine deaminase (ADA; EC 3.5.4.4) that catalyzes the deamination of adenosine and 2-prime-deoxyadenosine to inosine and deoxyinosine, respectively. Through their enzymatic action, ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors (see 102775). ADA2 shares highest sequence similarity with ADA-related growth factors, which are involved in tissue development (summary by Zavialov et al., 2010). ADA2 is a secreted homodimer highly expressed in plasma (summary by Navon Elkan et al., 2014). </p><p>Lee (2018) reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency (615688), which include vasculopathy, skin manifestations, neuropathy, immunodeficiency, and hematologic defects. </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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<h4>
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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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<span class="mim-text-font">
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<p>By exon trapping and genomic sequence analysis, Riazi et al. (2000) identified CECR1. They cloned the full-length cDNA by 5-prime RACE of total RNA from a lung cell line. The deduced protein contains 511 amino acids and shows sequence similarity to insect and mollusk growth factors. The N terminus contains a secretory signal peptide and the C-terminal half shows significant similarity to adenosine deaminase (ADA; 608958), particularly in the conserved catalytic domain. Northern blot analysis detected 1.0-, 3.5-, and 4.4-kb transcripts that were differentially expressed. Highest expression was in adult heart, lung, lymphoblasts, spleen, and placenta, as well as in fetal lung, liver, and kidney. Expression was weaker in adult pancreas, skeletal muscle, and liver, and faint in adult and fetal brain. In situ hybridization of a 35-day human embryo detected CECR1 mRNA in the outflow tract and atrium of the heart, the VII/VIII cranial nerve ganglion, the notochord, and the placenta. </p><p>Zavialov et al. (2010) determined that the putative 511-amino acid ADA2 protein contains an N-terminal signal peptide, a central ADA domain that covers over 70% of the mature ADA2 sequence, and several sites for N-glycosylation. The ADA domain of ADA2 shares 18 to 21% amino acid identity with the ADA1 (ADA) protein. </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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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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>Riazi et al. (2000) determined that CECR1 contains 9 exons and spans more than 28 kb, including a 2.2-kb 3-prime untranslated region that is rich in Alu and LINE repeats. </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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<h4>
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<span class="mim-font">
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<strong>Mapping</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>By genomic sequence analysis, Riazi et al. (2000) mapped the CECR1 gene within the cat eye syndrome (115470) critical region on chromosome 22q11.2. Southern blot analysis revealed that CECR1 is a single-copy gene. </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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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</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>Zavialov and Engstrom (2005) purified ADA2 from human plasma and from commercial IgG preparations. Mass spectrometric and database analyses revealed that ADA2 is identical to the CECR1 protein. In vitro, ADA2 showed a pH optimum of pH 6.8 and a Km of about 2.25 mM in the deamination of adenosine. Gel filtration analysis revealed that ADA2 formed homodimers with an apparent molecular mass of 110 kD. Monomers had an apparent molecular mass of 57 kD by SDS-PAGE. Zavialov and Engstrom (2005) found that ADA2 bound heparin in addition to IgG. </p><p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Zavialov et al. (2010) solved the crystal structures of human ADA2 apoenzyme and ADA2 homodimers complexed with a transition state analog to 2.0- and 2.5-angstrom resolution, respectively. The overall structure of the catalytic domain and catalytic site of ADA2 appeared similar to that of ADA1, suggesting the same catalytic mechanism. In ADA2, his86, his88, his330, and asp415 coordinated a zinc ion within the active-site cavity. The substrate-binding site in ADA2 appeared significantly different than that of ADA1. In contrast to the large conformational change observed in the active site of ADA1 upon substrate binding, little conformational change occurred in ADA2 dimers following binding to the transition state analog. ADA2 also assumed novel folds that mediated dimerization and binding to cell surface receptors. The highly conserved residues cys111 and cys133 within the ADA2 catalytic region formed a disulfide bond. Mutation of cys111 to gly or reduction of this disulfide bond reduced ADA2 secretion, led to massive aggregation of the protein, and reduced its ability to bind glycosaminoglycan. Oligosaccharide chains located on 3 different faces of ADA2 were positioned to protect the molecule against proteolysis in the extracellular space. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</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><strong><em>Vasculitis, Autoinflammation, Immunodeficiency, and Hematologic Defects Syndrome</em></strong></p><p>
|
|
In 9 patients from 8 unrelated families with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified homozygous or compound heterozygous mutations in the CECR1 gene (see, e.g., 607575.0001-607575.0006). All mutations except 1 were missense mutations. The initial mutations were found by whole-exome sequencing, and subsequent mutations were found by candidate gene sequencing. The disorder was characterized by onset of recurrent ischemic, and less frequently hemorrhagic, stroke affecting the small vessels of the brain and resulting in neurologic dysfunction. Patients also had recurrent fever and livedo racemosa. Brain and skin biopsies from patients showed evidence of endothelial damage associated with increased staining for IL1B (147720), TNFA (191160), and inducible nitric oxide synthase (NOS2A; 163730). Immunologic assessment of the patients, including laboratory studies of cell function and cytokine production, showed only mild abnormalities, such as hypogammaglobulinemia and increased B-cell death and reduced B-cell differentiation compared to controls. Patients had significantly decreased ADA2 activity in plasma, and Western blot analysis showed reduced ADA2 protein levels in cell lysates, consistent with a loss of function. ADA2 activity and protein levels in carrier parents were about 50% of normal. ADA1 (608958)-specific activity was preserved. Morpholino knockout of a CECR1 ortholog (cecr1b) in zebrafish resulted in intracranial bleeding that could be rescued by wildtype human CECR1, but not by mutant CECR1. Knockout of cecr1b in myeloid cells resulted in neutropenia. Knockdown of CECR1 using short hairpin RNA (shRNA) in human myeloid cells caused marked impairment of macrophage differentiation and disruption of cocultured monolayers of human microvascular endothelial cells. These defects in monocyte/macrophage differentiation were also seen in patients. Zhou et al. (2014) suggested that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and that ADA2 deficiency may polarize macrophages and monocytes toward proinflammatory cells, resulting in inflammation, endothelial cell damage, and small vessel vasculopathy. </p><p>In 19 patients of Georgian Jewish descent with autosomal recessive polyarteritis nodosa, Navon Elkan et al. (2014) identified a homozygous missense mutation in the CECR1 gene (G47R; 607575.0006). The mutation was found by exome sequencing. Affected members of a German family and a Turkish patient with a similar disorder were subsequently found to carry compound heterozygous missense CECR1 mutations (607575.0005; 607575.0007-607575.0009). ADA2 activity was significantly reduced in patient serum samples, and in vitro cellular expression studies showed low amounts of secreted mutant protein, consistent with a loss of function. There was considerable variability in the severity and age at onset, although most patients had onset of symptoms in the first decade. Patients had systemic involvement of the skin, nervous system, gastrointestinal tract, and kidneys. Features included stroke resulting in neurologic dysfunction, gastrointestinal pain, fever, elevated acute-phase proteins, myalgias, and livedo reticularis with an inflammatory vasculitis on biopsy. Some patients developed hypertension, aneurysms, or ischemic necrosis of the digits. </p><p><strong><em>Sneddon Syndrome</em></strong></p><p>
|
|
In 3 Portuguese sibs with Sneddon syndrome (SNDNS; 182410), previously reported by Mascarenhas et al. (2003), Bras et al. (2014) identified compound heterozygous missense mutations in the CECR1 gene (T119A, 607575.0010 and G142S, 607575.0011). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. The patients developed livedo racemosa, leg ulcerations, and intermittent fevers during the second decade of life, and had ischemic and/or hemorrhagic strokes in early adulthood. </p><p>In a 34-year-old woman with SNDNS, Tull et al. (2020) identified compound heterozygosity for mutations in the ADA2 gene (607575.0012, 607575.0013). One mutation was inherited from her mother and the other arose de novo. </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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<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>13 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 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</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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ADA2, TYR453CYS
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<br />
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SNP: rs376785840,
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|
|
|
|
|
gnomAD: rs376785840,
|
|
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|
|
|
ClinVar: RCV000106380, RCV002262702, RCV002477260
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated girls of European ancestry with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified compound heterozygous mutations in the CECR1 gene. Both patients carried a c.1358A-G transition in exon 9 of the CECR1 gene, resulting in a tyr453-to-cys (Y453C) substitution in a catalytic domain. The second mutation in 1 patient was a c.326C-A transversion in exon 3, resulting in an ala109-to-asp (A109D; 607575.0002) substitution in a catalytic domain, whereas the second mutation in the other patient was a c.140G-C transversion in exon 2, resulting in a gly47-to-ala (G47A; 607575.0003) substitution in the dimerization domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Candidate gene sequencing of additional patients with the disorder identified 1 who was compound heterozygous for Y453C and R169Q (607575.0005). Haplotype analysis indicated a founder effect for the Y453C mutation. All mutations occurred at highly conserved residues. The Y453C mutation was found in less than 1% of alleles in the Exome Variant Server database; it was not present in the dbSNP, 1000 Genomes Project, or ClinSeq 801 databases. Two Portuguese brothers among 94 patients with late-onset small-vessel ischemic stroke who were part of the Exome Variant Server database were found to carry a heterozygous Y453C mutation. The A109D mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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|
</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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<div>
|
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<span class="mim-text-font">
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ADA2, ALA109ASP
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|
<br />
|
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|
|
SNP: rs587777240,
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|
|
|
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|
|
ClinVar: RCV000106381
|
|
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|
</span>
|
|
</div>
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|
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|
|
<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the ala109-to-asp (A109D) mutation in the CECR1 gene that was found in compound heterozygous state in patients with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688) by Zhou et al. (2014), see 607575.0001. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, GLY47ALA ({dbSNP rs200930463})
|
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|
|
|
<br />
|
|
|
|
SNP: rs200930463,
|
|
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|
|
|
gnomAD: rs200930463,
|
|
|
|
|
|
ClinVar: RCV000106382, RCV001570811, RCV002483175, RCV004751262
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified compound heterozygous mutations in the CECR1 gene: a c.140G-C transversion in exon 2, resulting in a gly47-to-ala (G47A) substitution in the dimerization domain, and a c.336C-G transversion in exon 3, resulting in a his112-to-gln (H112Q; 607575.0004) substitution in a catalytic domain. Another patient with the disorder was compound heterozygous for G47A and Y453C (607575.0001). Both mutations occurred at highly conserved residues. Haplotype analysis indicated a founder effect for the G47A mutation. The G47A variant was found in less than 1% of alleles in the 1000 Genomes Project and ClinSeq 801 databases; it was not present in the Exome Variant Server database. The H112Q mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, HIS112GLN
|
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|
<br />
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|
|
|
SNP: rs587777241,
|
|
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|
|
|
gnomAD: rs587777241,
|
|
|
|
|
|
ClinVar: RCV000106383, RCV000722137, RCV002262703
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the his112-to-gln (H112Q) mutation in the CECR1 gene that was found in compound heterozygous state in a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688) by Zhou et al. (2014), see 607575.0003. </p>
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, ARG169GLN ({dbSNP rs77563738})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs77563738,
|
|
|
|
|
|
gnomAD: rs77563738,
|
|
|
|
|
|
ClinVar: RCV000106384, RCV001027542, RCV001091904, RCV001536077, RCV001808328, RCV002262704, RCV003945041
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified compound heterozygous mutations in the CECR1 gene: a c.506G-A transition in exon 3, resulting in an arg169-to-gln (R169Q) substitution in the PRB domain, and Y453C (607575.0001). Another patient with the disorder was compound heterozygous for R169Q and an intragenic 28-kb deletion. Both mutations occurred at highly conserved residues. Haplotype analysis indicated a founder effect for the R169Q mutation. The R169Q mutation was present in less than 1% of alleles in the 1000 Genomes Project and Exome Variant Server databases; it was not present in the ClinSeq 801 database. </p><p>In 4 German sibs with polyarteritis nodosa, Navon Elkan et al. (2014) identified compound heterozygous mutations in the CECR1 gene: R169Q and a c.752C-T transition, resulting in a pro251-to-leu (P251L; 607575.0007) substitution at a highly conserved residue. Each unaffected parent was heterozygous for 1 of the mutations. Among 4,300 European controls, the R169Q variant was found in 7 (0.0008) and the P251L variant was found in 1 (0.0001). Serum ADA2 activity in patients was severely reduced compared to controls. The R169Q protein was barely detectable in transfected cells. </p><p>Van Montfrans et al. (2016) identified a homozygous R169Q mutation in the ADA2 gene in 9 patients from 6 unrelated families from the Netherlands with highly variable presentations and manifestations. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, GLY47ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs202134424,
|
|
|
|
|
|
gnomAD: rs202134424,
|
|
|
|
|
|
ClinVar: RCV000106385, RCV001091906, RCV002262705, RCV002498474, RCV003445509
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 Turkish patients, including 2 sibs, with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified a homozygous c.139G-A transition in exon 2 of the CECR1 gene, resulting in a gly47-to-arg (G47R) substitution at a highly conserved residue in the dimerization domain. Haplotype analysis indicated a founder effect, and the carrier frequency of this variant in Turkish controls was 0.002. The G47R mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. </p><p>Navon Elkan et al. (2014) identified a homozygous G47R mutation in 19 Georgian Jewish individuals with polyarteritis nodosa. Sixteen of the patients were from 5 multiplex families, and 3 patients had apparently sporadic disease. Fifteen of the patients were diagnosed before 10 years of age, including 6 in infancy. In contrast, 1 patient had onset of the disorder with leg ulcers at age 59 years. The mutation, which was found by exome sequencing in the initial patients and later found and confirmed by Sanger sequencing in the other patients, was not present in 864 in-house exomes or in more than 7,500 exome sequences present in public databases. Among 246 unrelated Georgian Jewish controls, 25 were heterozygous for the mutation, yielding a carrier frequency of 0.102 in this population. Serum ADA2 activity in homozygous mutation carriers was reduced by a factor of more than 4 compared to controls. Transfection of the mutation into Drosophila cells resulted in decreased expression of the mutant protein compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, PRO251LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs148936893,
|
|
|
|
|
|
gnomAD: rs148936893,
|
|
|
|
|
|
ClinVar: RCV000106386, RCV001781437, RCV005025173
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the pro251-to-leu (P251L) mutation in the CECR1 gene that was found in compound heterozygous state in patients with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688) by Navon Elkan et al. (2014), see 607575.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, GLY47VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200930463,
|
|
|
|
|
|
gnomAD: rs200930463,
|
|
|
|
|
|
ClinVar: RCV000106387, RCV000481270, RCV002505023
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish man with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Navon Elkan et al. (2014) identified compound heterozygous mutations in the CECR1 gene: a c.140G-T transversion, resulting in a gly47-to-val (G47V) substitution, and a c.791G-C transversion, resulting in a trp264-to-ser (W264S; 607575.0009) substitution. Both mutations occurred at highly conserved residues. Each unaffected parent was heterozygous for 1 of the mutations, and neither mutation was found in 200 Turkish controls or in more than 7,500 exome sequences present in public databases. The mutant G47V protein was barely detectable in transfected cells, and the W264S mutant protein was retained intracellularly, resulting in decreased secretion of ADA2 into the media. Transfection of the G47V mutation into Drosophila cells resulted in decreased expression of the mutant protein; the W264S mutation caused decreased stability of the mutant protein compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, TRP264SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777242,
|
|
|
|
|
|
|
|
ClinVar: RCV000106388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the trp264-to-ser (W264S) mutation in the CECR1 gene that was found in compound heterozygous state in a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688) by Navon Elkan et al. (2014), see 607575.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SNEDDON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, THR119ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs775440641,
|
|
|
|
|
|
gnomAD: rs775440641,
|
|
|
|
|
|
ClinVar: RCV000169758, RCV000851530, RCV004584361
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 Portuguese sibs with Sneddon syndrome (SNDNS; 182410), previously reported by Mascarenhas et al. (2003), Bras et al. (2014) identified compound heterozygous mutations in the CECR1 gene: a c.355A-G transition, resulting in a thr119-to-ala (T119A) substitution, and a c.424G-A transition, resulting in a gly142-to-ser (G142S; 607575.0011) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SNEDDON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, GLY142SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs770689762,
|
|
|
|
|
|
gnomAD: rs770689762,
|
|
|
|
|
|
ClinVar: RCV000169759, RCV001386673, RCV002460949, RCV002485053
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.424G-A transition in the CECR1 gene, resulting in a gly142-to-ser (G142S) substitution, that was found in compound heterozygous state in patients with Sneddon syndrome (SNDNS; 182410) by Bras et al. (2014), see 607575.0010. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 SNEDDON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ADA2, PHE212DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2123699776,
|
|
|
|
|
|
|
|
ClinVar: RCV001523887
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 34-year-old woman with Sneddon syndrome (SNDNS; 182410), Tull et al. (2020) identified compound heterozygosity for mutations in the ADA2 gene: the first was a 3-bp in-frame deletion (c.634_636delTTC), resulting in deletion of the phe212 residue (F212del), and the second was a c.1225C-T transition resulting in a pro409-to-ser (P409S; 607575.0013) substitution. Her unaffected mother was heterozygous for the deletion, but no ADA2 mutations were detected in her father, indicating a de novo origin for the missense mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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<h4>
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<span class="mim-font">
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<strong>.0013 SNEDDON SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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ADA2, PRO409SER
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<br />
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SNP: rs777618863,
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gnomAD: rs777618863,
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ClinVar: RCV001523888, RCV001872009
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</span>
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</div>
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<span class="mim-text-font">
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<p>For discussion of the c.1225C-T transition in the ADA2 gene, resulting in a pro409-to-ser (P409S) substitution, that was found in compound heterozygous state in a 34-year-old woman with Sneddon syndrome (SNDNS; 182410) by Tull et al. (2020), see 607575.0012. </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>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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Bras, J., Guerreiro, R., Santo, G. C.
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<strong>Mutant ADA2 in vasculopathies. (Letter)</strong>
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New Eng. J. Med. 371: 478-480, 2014.
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[PubMed: 25075847]
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[Full Text: https://doi.org/10.1056/NEJMc1405506]
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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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Lee, P. Y.
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<strong>Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2.</strong>
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Front. Pediat. 6: 282, 2018. Note: Electronic Article.
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[PubMed: 30406060]
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[Full Text: https://doi.org/10.3389/fped.2018.00282]
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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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Mascarenhas, R., Santo, G., Goncalo, M., Ferro, M. A., Tellechea, O., Figueiredo, A.
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<strong>Familial Sneddon's syndrome.</strong>
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Europ. J. Derm. 13: 283-287, 2003.
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[PubMed: 12804991]
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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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Navon Elkan, P., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., Zlotogorski, A., Berkun, Y., Press, J. J., Mukamel, M., Voth, I., Hashkes, P. J., and 23 others.
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<strong>Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.</strong>
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New Eng. J. Med. 370: 921-931, 2014.
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[PubMed: 24552285]
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[Full Text: https://doi.org/10.1056/NEJMoa1307362]
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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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Riazi, M. A., Brinkman-Mills, P., Nguyen, T., Pan, H., Phan, S., Ying, F., Roe, B. A., Tochigi, J., Shimizu, Y., Minoshima, S., Shimizu, N., Buchwald, M., McDermid, H. E.
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<strong>The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome.</strong>
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Genomics 64: 277-285, 2000.
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[PubMed: 10756095]
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[Full Text: https://doi.org/10.1006/geno.1999.6099]
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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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Tull, T. J., Martin, B., Spencer, J., Sangle, S., Chua, S., McGrath, J. A., D'Cruz, D. P., McGibbon, D. H.
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<strong>Sneddon syndrome associated with two novel ADA2 gene mutations.</strong>
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Rheumatology 59: 1448-1450, 2020.
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[PubMed: 31652311]
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[Full Text: https://doi.org/10.1093/rheumatology/kez446]
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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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van Montfrans, J. M., Hartman, E. A. R., Braun, K. P. J., Hennekam, E. A. M., Hak, E. A., Nederkoorn, P. J., Westendorp, W. F., Bredius, R. G. M., Kollen, W. J. W., Scholvinck, E. H., Legger, G. E., Meyts, I.
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<strong>Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.</strong>
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Rheumatology 55: 902-910, 2016.
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[PubMed: 26867732]
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[Full Text: https://doi.org/10.1093/rheumatology/kev439]
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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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Zavialov, A. V., Engstrom, A.
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<strong>Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity.</strong>
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Biochem. J. 391: 51-57, 2005.
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[PubMed: 15926889]
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[Full Text: https://doi.org/10.1042/BJ20050683]
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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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Zavialov, A. V., Yu, X., Spillmann, D., Lauvau, G., Zavialov, A. V.
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<strong>Structural basis for the growth factor activity of human adenosine deaminase ADA2.</strong>
|
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J. Biol. Chem. 285: 12367-12377, 2010.
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[PubMed: 20147294]
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[Full Text: https://doi.org/10.1074/jbc.M109.083527]
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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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Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., Stone, D. L., Chae, J. J., Rosenzweig, S. D., Bishop, K., Barron, K. S., Kuehn, H. S., and 52 others.
|
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<strong>Early-onset stroke and vasculopathy associated with mutations in ADA2.</strong>
|
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New Eng. J. Med. 370: 911-920, 2014.
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[PubMed: 24552284]
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[Full Text: https://doi.org/10.1056/NEJMoa1307361]
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</p>
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</li>
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</ol>
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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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<div class="row">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Marla J. F. O'Neill - updated : 06/14/2021<br>Cassandra L. Kniffin - updated : 04/03/2019<br>Cassandra L. Kniffin - updated : 8/4/2014<br>Cassandra L. Kniffin - updated : 3/11/2014<br>Patricia A. Hartz - updated : 12/14/2010
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</span>
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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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Patricia A. Hartz : 2/24/2003
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</span>
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alopez : 06/16/2021<br>alopez : 06/14/2021<br>carol : 05/05/2021<br>carol : 04/04/2019<br>carol : 04/03/2019<br>ckniffin : 04/03/2019<br>mgross : 01/31/2019<br>carol : 03/28/2016<br>mcolton : 4/7/2015<br>carol : 8/6/2014<br>carol : 8/6/2014<br>mcolton : 8/6/2014<br>ckniffin : 8/4/2014<br>alopez : 3/26/2014<br>mcolton : 3/12/2014<br>ckniffin : 3/11/2014<br>mgross : 1/10/2011<br>terry : 12/14/2010<br>ckniffin : 10/28/2004<br>mgross : 2/24/2003
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