5717 lines
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Entry
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- *301300 - DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*301300</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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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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<a href="#geneFunction">Gene Function</a>
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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/301300">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000158578;t=ENST00000650242" 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=212" 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=301300" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000158578;t=ENST00000650242" 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_000032,NM_001037967,NM_001037968" 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_000032" 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=301300" 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=02356&isoform_id=02356_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/ALAS2" 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/28586,28588,3220249,20141346,28300418,47059369,47059371,47059373,47059375,47059377,47059379,47059381,47059383,47059385,47059387,47059389,47059391,47059393,47059395,47059397,47059399,47059401,47059403,47059405,47059407,47059409,47059411,47059413,47059415,47059417,47059419,47059421,47059423,47059425,47059427,47059429,47059431,47059433,47059435,47059437,47059439,47059441,47059443,47059445,47059447,47059449,83977440,83977442,83977444,112180419,119613617,119613618,119613619,158254562,158256610,189053687" 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/P22557" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=212" 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=ENSG00000158578;t=ENST00000650242" 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=ALAS2" 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=ALAS2" 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+212" 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/ALAS2" 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:212" 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/212" 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=chrX&hgg_gene=ENST00000650242.1&hgg_start=55009055&hgg_end=55030977&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:397" 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/alas2" 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=301300[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=301300[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000158578" 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=ALAS2" 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=ALAS2" 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=ALAS2" 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=ALAS2&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/PA24689" 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:397" 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/FBgn0020764.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:87990" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ALAS2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:87990" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/212/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=212" 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-001229-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:301300" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:212" 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=ALAS2&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> 1197360001, 48983004<br />
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<strong>ICD10CM:</strong> D64.0<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>
|
|
301300
|
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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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DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ALAS, ERYTHROID; ALASE<br />
|
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5-AMINOLEVULINATE SYNTHASE, ERYTHROID-SPECIFIC
|
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</span>
|
|
</h4>
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ALAS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ALAS2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/X/341?start=-3&limit=10&highlight=341">Xp11.21</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:55009055-55030977&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'})">X:55,009,055-55,030,977</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
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|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300751,300752" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/341?start=-3&limit=10&highlight=341">
|
|
Xp11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Anemia, sideroblastic, 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300751"> 300751 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Delta-aminolevulinate synthase (ALAS; <a href="https://enzyme.expasy.org/EC/2.3.1.27" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.3.1.27</a>) catalyzes the first committed step of heme biosynthesis, which is the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5-phosphate (PLP)-dependent manner (<a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al., 2005</a>). Two forms of ALAS exist in humans: a housekeeping form encoded by the ALAS1 gene (<a href="/entry/125290">125290</a>), and an erythroid tissue-specific form encoded by the ALAS2 gene (<a href="#8" class="mim-tip-reference" title="Bishop, D. F., Henderson, A. S., Astrin, K. H. <strong>Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome.</strong> Genomics 7: 207-214, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347585</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90542-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2347585">Bishop et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16121195+2347585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Astrin, K. H., Bishop, D. F. <strong>Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to the X chromosome. (Abstract)</strong> Cytogenet. Cell Genet. 51: 953-954, 1989."None>Astrin and Bishop (1989)</a> isolated the ALAS2 gene from an erythroid human fetal liver library. ALAS2 appeared to be expressed only in erythroid cells.</p>
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<p><a href="#34" class="mim-tip-reference" title="Surinya, K. H., Cox, T. C., May, B. K. <strong>Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene.</strong> J. Biol. Chem. 273: 16798-16809, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9642238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9642238</a>] [<a href="https://doi.org/10.1074/jbc.273.27.16798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9642238">Surinya et al. (1998)</a> determined that the ALAS2 gene spans about 35 kb and contains 11 exons. An erythroid-specific enhancer in intron 8 contains GATA and CACCC boxes that are conserved in mouse and canine Alas2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9642238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Benoff, S., Skoultchi, A. I. <strong>X-linked control of hemoglobin production in somatic hybrids of mouse erythroleukemic cells and mouse lymphoma or bone marrow cells.</strong> Cell 12: 263-274, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/561665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">561665</a>] [<a href="https://doi.org/10.1016/0092-8674(77)90204-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="561665">Benoff and Skoultchi (1977)</a> presented 3 lines of evidence that a locus on the X chromosome in the mouse controls hemoglobin synthesis. Following Ohno's law, one would expect the same locus to exist in man. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=561665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Benoff, S., Bruce, S. A., Skoultchi, A. I. <strong>Negative control of hemoglobin production in somatic cell hybrids due to heme deficiency.</strong> Proc. Nat. Acad. Sci. 75: 4354-4358, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/279921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">279921</a>] [<a href="https://doi.org/10.1073/pnas.75.9.4354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="279921">Benoff et al. (1978)</a> identified in the mouse an X-linked locus that inhibits hemoglobin production by inhibiting inducible heme biosynthesis, probably at the step catalyzed by delta-aminolevulinic acid synthetase. Close linkage to the Xg locus was excluded by <a href="#24" class="mim-tip-reference" title="Elves, M. W., Bourne, M. S., Israels, M. C. G. <strong>Pyridoxine-responsive anaemia determined by an X-linked gene.</strong> J. Med. Genet. 3: 1-4, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5911826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5911826</a>] [<a href="https://doi.org/10.1136/jmg.3.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5911826">Elves et al. (1966)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=279921+5911826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Astrin, K. H., Desnick, R. J., Bishop, D. F. <strong>Assignment of human delta-aminolevulinate synthase (ALAS) to chromosome 3. (Abstract)</strong> Cytogenet. Cell Genet. 46: 573, 1987."None>Astrin et al. (1987)</a> mapped the ALAS1 gene to chromosome 3, excluding it as a candidate gene for X-linked hypochromic anemia. Later, however, <a href="#3" class="mim-tip-reference" title="Astrin, K. H., Bishop, D. F. <strong>Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to the X chromosome. (Abstract)</strong> Cytogenet. Cell Genet. 51: 953-954, 1989."None>Astrin and Bishop (1989)</a> isolated a second ALAS gene, ALAS2, and by Southern blot analysis of DNAs from somatic cell hybrids, assigned it to the X chromosome. Also see <a href="#8" class="mim-tip-reference" title="Bishop, D. F., Henderson, A. S., Astrin, K. H. <strong>Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome.</strong> Genomics 7: 207-214, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347585</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90542-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2347585">Bishop et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2347585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Southern analysis of a mouse/human hybrid cell panel and by in situ hybridization, <a href="#19" class="mim-tip-reference" title="Cox, T. C., Bawden, M. J., Abraham, N. G., Bottomley, S. S., May, B. K., Baker, E., Chen, L. Z., Sutherland, G. R. <strong>Erythroid 5-aminolevulinate synthase is located on the X chromosome.</strong> Am. J. Hum. Genet. 46: 107-111, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2294742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2294742</a>]" pmid="2294742">Cox et al. (1990)</a> mapped the ALAS2 gene to chromosome Xp21-q21, with the most likely location being on band Xp11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2294742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of DNA from hybrid clones containing translocations in the region Xp11.21-q21.3, <a href="#18" class="mim-tip-reference" title="Cotter, P. D., Willard, H. F., Gorski, J. L., Bishop, D. F. <strong>Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X;autosome translocations.</strong> Genomics 13: 211-212, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577484</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90223-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577484">Cotter et al. (1992)</a> achieved finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. They localized the ALAS2 gene to subregion Xp11.21. <a href="#21" class="mim-tip-reference" title="Cox, T. C., Kozman, H. M., Raskind, W. H., May, B. K., Mulley, J. C. <strong>Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia.</strong> Hum. Molec. Genet. 1: 639-641, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301172</a>] [<a href="https://doi.org/10.1093/hmg/1.8.639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301172">Cox et al. (1992)</a> identified a highly polymorphic marker, a compound dinucleotide repeat, within intron 7 of the ALAS2 gene and used it to confirm the localization of ALAS2 in the multipoint linkage map of the X chromosome. No recombination was observed between ALAS2 and the centromere marker DXZ1. No recombination was found with DXS14. Since <a href="#33" class="mim-tip-reference" title="Raskind, W. H., Wijsman, E., Pagon, R. A., Cox, T. C., Bawden, M. J., May, B. K., Bird, T. D. <strong>X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.</strong> Am. J. Hum. Genet. 48: 335-341, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671320</a>]" pmid="1671320">Raskind et al. (1991)</a> excluded linkage of DXS14 and X-linked sideroblastic anemia with spinocerebellar ataxia within 5 to 10 cM, one can probably conclude that there are at least 2 loci on the X chromosome determining sideroblastic anemia. One locus may be located on the proximal portion of Xq. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1301172+1671320+1577484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, <a href="#9" class="mim-tip-reference" title="Blair, H. J., Ho, M., Monaco, A. P., Fisher, S., Craig, I. W., Boyd, Y. <strong>High-resolution comparative mapping of the proximal region of the mouse X chromosome.</strong> Genomics 28: 305-310, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530041</a>] [<a href="https://doi.org/10.1006/geno.1995.1146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530041">Blair et al. (1995)</a> demonstrated the location of the Alas2 gene relative to others. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8530041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using a reporter gene assay, <a href="#34" class="mim-tip-reference" title="Surinya, K. H., Cox, T. C., May, B. K. <strong>Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene.</strong> J. Biol. Chem. 273: 16798-16809, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9642238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9642238</a>] [<a href="https://doi.org/10.1074/jbc.273.27.16798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9642238">Surinya et al. (1998)</a> showed that intron 8 of the ALAS2 gene harbored strong orientation-dependent erythroid-specific enhancer activity. In vitro assays showed that GATA1 (<a href="/entry/305371">305371</a>) and SP1 (<a href="/entry/189906">189906</a>) bound the GATA and CACCC boxes within this region, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9642238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Han, L., Lu, J., Pan, L., Wang, X., Shao, Y., Han, S., Huang, B. <strong>Histone acetyltransferase p300 regulates the transcription of human erythroid-specific 5-aminolevulinate synthase gene.</strong> Biochem. Biophys. Res. Commun. 348: 799-806, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16904069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16904069</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.07.147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16904069">Han et al. (2006)</a> showed that histone deacetylase (HDAC; see <a href="/entry/601241">601241</a>) inhibitors increased ALAS2 expression in a human erythroid cell line. Increased ALAS2 expression was concurrent with increased acetylation of histone H4 (see <a href="/entry/602822">602822</a>) at the ALAS2 promoter. Histone acetyltransferase p300 (EP300; <a href="/entry/602700">602700</a>) bound the ALAS2 promoter, and overexpression of p300 increased promoter reporter expression and endogenous ALAS2 mRNA levels. The GATA1 and SP1 sites at the ALAS2 promoter synergistically contributed to p300-mediated ALAS2 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16904069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined the crystal structure of homodimeric Alas from Rhodobacter capsulatus, which shares 49% sequence identity with human ALAS. Mutations in the ALAS gene resulting in X-linked sideroblastic anemia were predicted to obstruct substrate binding, disrupt the dimer interface, or hamper proper folding (see, e.g., <a href="#0002">301300.0002</a>-<a href="#0005">301300.0005</a>). The findings provided explanations for potential responsiveness to pyridoxine treatment in some cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Sideroblastic Anemia 1, X-Linked</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Aoki, Y., Urata, G., Takaku, F. <strong>Delta-aminolevulinic acid synthetase activity in erythroblasts of patients with primary sideroblastic anemia.</strong> Acta Haemat. Jpn. 36: 74-77, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4738994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4738994</a>]" pmid="4738994">Aoki et al. (1973)</a> found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), some of whom were males with congenital anemia which in some responded to treatment with vitamin B6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4738994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia, <a href="#14" class="mim-tip-reference" title="Cotter, P. D., Baumann, M., Bishop, D. F. <strong>Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.</strong> Proc. Nat. Acad. Sci. 89: 4028-4032, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570328</a>] [<a href="https://doi.org/10.1073/pnas.89.9.4028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570328">Cotter et al. (1992)</a> identified a mutation in the ALAS2 gene (<a href="#0001">301300.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Cotter, P. D., May, A., Fitzsimons, E. J., Houston, T., Woodcock, B. E., Al-Sabah, A. I., Wong, L., Bishop, D. F. <strong>Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.</strong> J. Clin. Invest. 96: 2090-2096, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560104</a>] [<a href="https://doi.org/10.1172/JCI118258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560104">Cotter et al. (1995)</a> described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. She was found to be heterozygous for a point mutation of the ALAS2 gene (<a href="#0005">301300.0005</a>). The initial diagnosis was myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. There is evidence from other sources that skewed lyonization can be an acquired pattern. In the study of peripheral blood leukocytes by <a href="#10" class="mim-tip-reference" title="Busque, L., Mio, R., Mattioli, J., Brais, E., Blais, N., Lalonde, Y., Maragh, M., Gilliland, D. G. <strong>Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.</strong> Blood 88: 59-65, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8704202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8704202</a>]" pmid="8704202">Busque et al. (1996)</a>, the incidence of skewing was 1.9% in neonates, 4.5% in women who were 28 to 32 years old, and 22.7% in women who were 60 years of age or older. <a href="#11" class="mim-tip-reference" title="Cazzola, M., Bergamaschi, G. <strong>X-linked Wiskott-Aldrich syndrome in a girl. (Letter)</strong> New Eng. J. Med. 338: 1850 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634367</a>] [<a href="https://doi.org/10.1056/NEJM199806183382515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634367">Cazzola and Bergamaschi (1998)</a> estimated that in 30 to 40% of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90% expression of 1 parental X chromosome. <a href="#32" class="mim-tip-reference" title="Puck, J. M., Willard, H. F. <strong>X inactivation in females with X-linked disease.</strong> New Eng. J. Med. 338: 325-327, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9445416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9445416</a>] [<a href="https://doi.org/10.1056/NEJM199801293380611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9445416">Puck and Willard (1998)</a> reviewed mechanisms for a skewed pattern with a diagram of 3 different mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8704202+9445416+7560104+9634367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 each of 4 unrelated males with X-linked sideroblastic anemia, <a href="#16" class="mim-tip-reference" title="Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. <strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong> Blood 93: 1757-1769, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10029606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10029606</a>]" pmid="10029606">Cotter et al. (1999)</a> identified new mutations: 647T-C, 1283C-T, 1395G-A, and 1406C-T predicting amino acid substitutions tyr199 to his (Y199H; <a href="#0017">301300.0017</a>), arg411 to cys (R411C; <a href="#0008">301300.0008</a>), arg448 to gln (R448Q), and arg452 to cys (R452C; <a href="#0018">301300.0018</a>), respectively. All probands were clinically pyridoxine-responsive. The Y199H mutation was demonstrated to be the first de novo XLSA mutation, having occurred in a gamete of the proband's maternal grandfather. In 18 unrelated XLSA hemizygotes, <a href="#16" class="mim-tip-reference" title="Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. <strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong> Blood 93: 1757-1769, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10029606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10029606</a>]" pmid="10029606">Cotter et al. (1999)</a> found a significantly higher frequency of coinheritance of the hereditary hemochromatosis HFE mutant allele C282Y (<a href="/entry/235200#0001">235200.0001</a>) than found in the normal population. One proband with the Y199H mutation with severe and early iron loading was homozygous for C282Y. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10029606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 81-year-old man who developed sideroblastic anemia while undergoing hemodialysis, <a href="#26" class="mim-tip-reference" title="Furuyama, K., Harigae, H., Kinoshita, C., Shimada, T., Miyaoka, K., Kanda, C., Maruyama, Y., Shibahara, S., Sassa, S. <strong>Late-onset X-linked sideroblastic anemia following hemodialysis.</strong> Blood 101: 4623-4624, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531813</a>] [<a href="https://doi.org/10.1182/blood-2002-09-2804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531813">Furuyama et al. (2003)</a> identified heterozygosity for an asp159-to-asn change in the ALAS2 gene (D159N; <a href="#0012">301300.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Erythropoietic Protoporphyria, X-Linked</em></strong></p><p>
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In 8 families with X-linked dominant erythropoietic protoporphyria (XLEPP; <a href="/entry/300752">300752</a>), <a href="#35" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> identified 2 deletion mutations in exon 11 of the ALAS2 gene (<a href="#0015">301300.0015</a> and <a href="#0016">301300.0016</a>). The mutations were not found in 129 unrelated patients with other forms of erythropoietic protoporphyria or 100 normal chromosomes. The data of <a href="#35" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> demonstrated that disruption of the C-terminal region of ALAS2 leads to the production of protoporphyrin in excess of the amount required for hemoglobinization and in quantities sufficient to cause photosensitivity and liver damage, in spite of normal ferrochelatase (FECH; <a href="/entry/612386">612386</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 unrelated girls with X-linked dominant erythropoietic protoporphyria, <a href="#22" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; <a href="#0015">301300.0015</a>) and the other 2 were novel (<a href="#0019">301300.0019</a> and <a href="#0020">301300.0020</a>). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. All 4 girls presented in early childhood with severe photosensitivity associated with increased erythrocyte zinc- and metal-free protoporphyrin. Two had elevated liver enzymes, 1 had gallstones, and most had iron deficiency. The mother of 1 child was mildly affected and was shown to be somatic and germline mosaic for the mutation. By generating a series of ALAS2 variants, <a href="#22" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=301300[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 ANEMIA, SIDEROBLASTIC, 1</strong>
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ALAS2, ILE471ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852299 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852299;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=rs137852299" 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=rs137852299" 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=RCV000011214" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011214" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011214</a>
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<p>In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#14" class="mim-tip-reference" title="Cotter, P. D., Baumann, M., Bishop, D. F. <strong>Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.</strong> Proc. Nat. Acad. Sci. 89: 4028-4032, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570328</a>] [<a href="https://doi.org/10.1073/pnas.89.9.4028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570328">Cotter et al. (1992)</a> identified a T-to-A transition in codon 471 in a highly conserved region of exon 9 of the ALAS gene, resulting in an ile-to-asn substitution. The mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of beta-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs showed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5-prime-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5-prime-phosphate binding site. To identify the mutation, <a href="#14" class="mim-tip-reference" title="Cotter, P. D., Baumann, M., Bishop, D. F. <strong>Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.</strong> Proc. Nat. Acad. Sci. 89: 4028-4032, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570328</a>] [<a href="https://doi.org/10.1073/pnas.89.9.4028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570328">Cotter et al. (1992)</a> amplified and sequenced the 11 exonic coding regions of the ALAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 ANEMIA, SIDEROBLASTIC, 1</strong>
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ALAS2, THR388SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852300 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852300;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=rs137852300" 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=rs137852300" 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=RCV000011215" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011215" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011215</a>
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<p>In 2 affected males and 1 carrier female in a kindred with X-linked pyridoxine-responsive sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#20" class="mim-tip-reference" title="Cox, T. C., Bottomley, S. S., Wiley, J. S., Bawden, M. J., Matthews, C. S., May, B. K. <strong>X-linked pyridoxine-responsive sideroblastic anemia due to a thr388-to-ser substitution in erythroid 5-aminolevulinate synthase.</strong> New Eng. J. Med. 330: 675-679, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8107717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8107717</a>] [<a href="https://doi.org/10.1056/NEJM199403103301004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8107717">Cox et al. (1994)</a> demonstrated a cytosine-to-guanine change at nucleotide 1215 in exon 8. This change resulted in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wildtype. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appeared to introduce a conformational change at the active site of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8107717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, <a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined that thr388 is part of the PLP recognition pattern. Substitution of threonine by serine would allow for higher rotational freedom of serine, significantly reducing the affinity of ALAS for PLP. Correspondingly, patients would respond favorably to pyridoxine treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 ANEMIA, SIDEROBLASTIC, 1</strong>
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ALAS2, PHE165LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852301 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852301;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=rs137852301" 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=rs137852301" 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=RCV000011216 OR RCV001857329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011216, RCV001857329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011216...</a>
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<p>In the original family with X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>) described by <a href="#13" class="mim-tip-reference" title="Cooley, T. B. <strong>A severe type of hereditary anemia with elliptocytosis: interesting sequence of splenectomy.</strong> Am. J. Med. Sci. 209: 561-568, 1945."None>Cooley (1945)</a>, <a href="#17" class="mim-tip-reference" title="Cotter, P. D., Rucknagel, D. L., Bishop, D. F. <strong>X-linked sideroblastic anemia: identification of the mutation in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) in the original family described by Cooley.</strong> Blood 84: 3915-3924, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7949148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7949148</a>]" pmid="7949148">Cotter et al. (1994)</a> found that the ALAS2 gene harbored an A-to-C transversion in exon 5, predicted to result in the substitution of leucine for phenylalanine at residue 165 (F165L). The mutation occurred in the first highly conserved domain of the ALAS2 catalytic core shared by all species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7949148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, <a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined that phe165 structurally stabilizes the neighboring arg163, required for sCoA carboxylate group recognition, through hydrophobic interactions. Replacing phe165 by leucine destabilizes arg163, reducing the specificity of sCoA binding. As PLP binding is not affected by the mutation, response to pyridoxine treatment was predicted to be marginal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ANEMIA, SIDEROBLASTIC, 1</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">rs137852302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852302;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=rs137852302" 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=rs137852302" 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=RCV000011217" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011217" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011217</a>
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<p>In a large kindred with a pyridoxine-sensitive form of X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#31" class="mim-tip-reference" title="Prades, E., Chambon, C., Dailey, T. A., Dailey, H. A., Briere, J., Grandchamp, B. <strong>A new mutation of the ALAS2 gene in a large family with X-linked sideroblastic anemia.</strong> Hum. Genet. 95: 424-428, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7705839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7705839</a>] [<a href="https://doi.org/10.1007/BF00208968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7705839">Prades et al. (1995)</a> found a G-to-A transition at nucleotide 871 of the coding sequence (exon 7) of the ALAS2 gene. This resulted in a gly291-to-ser amino acid substitution. The glycine is conserved through evolution in ALAS proteins deduced from DNA sequences of a large number of different organisms. With a PCR assay, they demonstrated the mutation in 3 affected males and 2 female carriers, whereas the carrier status was excluded in 8 females at risk. Early detection of the mutant allele in family members may be important for the prevention of anemia in males and of ion overload both in affected males and carrier females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7705839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, <a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined that replacement of gly291 by ser would decrease the affinity of ALAS for sCoA. Furthermore, gly291 is 1 helical turn away from his285, which is involved in PLP binding. As a result, this mutation may be counteracted by increasing levels of PLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET</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">rs137852303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852303;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=rs137852303" 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=rs137852303" 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=RCV000011218" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011218" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011218</a>
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<p><a href="#15" class="mim-tip-reference" title="Cotter, P. D., May, A., Fitzsimons, E. J., Houston, T., Woodcock, B. E., Al-Sabah, A. I., Wong, L., Bishop, D. F. <strong>Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.</strong> J. Clin. Invest. 96: 2090-2096, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560104</a>] [<a href="https://doi.org/10.1172/JCI118258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560104">Cotter et al. (1995)</a> reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A-to-C transversion in exon 7 (K299Q) of the ALAS2 gene in the man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; <a href="#0006">301300.0006</a>). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. <a href="#15" class="mim-tip-reference" title="Cotter, P. D., May, A., Fitzsimons, E. J., Houston, T., Woodcock, B. E., Al-Sabah, A. I., Wong, L., Bishop, D. F. <strong>Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.</strong> J. Clin. Invest. 96: 2090-2096, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560104</a>] [<a href="https://doi.org/10.1172/JCI118258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560104">Cotter et al. (1995)</a> suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7560104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, <a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET</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> rs137852304 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852304;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/rs137852304?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=rs137852304" 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=rs137852304" 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=RCV000011219 OR RCV001729346" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011219, RCV001729346" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011219...</a>
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<p>See <a href="#0005">301300.0005</a> and <a href="#15" class="mim-tip-reference" title="Cotter, P. D., May, A., Fitzsimons, E. J., Houston, T., Woodcock, B. E., Al-Sabah, A. I., Wong, L., Bishop, D. F. <strong>Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.</strong> J. Clin. Invest. 96: 2090-2096, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560104</a>] [<a href="https://doi.org/10.1172/JCI118258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560104">Cotter et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7560104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY</strong>
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ALAS2, ASP190VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935484 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935484;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=rs28935484" 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=rs28935484" 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=RCV003322588" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003322588" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003322588</a>
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<p>In a patient with X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#25" class="mim-tip-reference" title="Furuyama, K., Fujita, H., Nagai, T., Yomogida, K., Munakata, H., Kondo, M., Kimura, A., Kuramoto, A., Hayashi, N., Yamamoto, M. <strong>Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene.</strong> Blood 90: 822-830, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9226183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9226183</a>]" pmid="9226183">Furuyama et al. (1997)</a> identified a 621A-T transversion in the ALAS2 gene that led to an asp190-to-val amino acid substitution. The anemia was refractory to pyridoxine treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9226183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 ANEMIA, SIDEROBLASTIC, 1</strong>
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ALAS2, ARG411CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852305;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=rs137852305" 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=rs137852305" 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=RCV000011221 OR RCV003555997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011221, RCV003555997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011221...</a>
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<p>In a Japanese patient with pyridoxine-responsive X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#27" class="mim-tip-reference" title="Furuyama, K., Uno, R., Urabe, A., Hayashi, N., Fujita, H., Kondo, M., Sassa, S., Yamamoto, M. <strong>R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity.</strong> Brit. J. Haemat. 103: 839-841, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9858242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9858242</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1998.01050.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9858242">Furuyama et al. (1998)</a> identified an arg411-to-cys missense mutation of the ALAS2 gene. The normal and mutant cDNAs were expressed in E. coli, and mutant enzyme protein was found to have 12% and 25% ALAS activity when incubated in the absence and presence of pyridoxal 5-prime-phosphate, respectively, compared with that of the wildtype enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9858242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 ANEMIA, SIDEROBLASTIC, 1</strong>
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ALAS2, SER568GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852306 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852306;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=rs137852306" 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=rs137852306" 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=RCV000011222" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011222" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011222</a>
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<p>In an 18-year-old Japanese male with sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#29" class="mim-tip-reference" title="Harigae, H., Furuyama, K., Kimura, A., Neriishi, K., Tahara, N., Kondo, M., Hayashi, N., Yamamoto, M., Sassa, S., Sasaki, T. <strong>A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia.</strong> Brit. J. Haemat. 106: 175-177, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10444183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10444183</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01479.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10444183">Harigae et al. (1999)</a> identified a 1754A-G missense mutation in exon 11 of the ALAS2 gene, resulting in a ser568-to-gly amino acid substitution. ALAS activity in bone marrow cells of the patient was reduced to 53.3% of the normal control. Consistent with this finding, activity of a bacterially expressed ALAS2 mutant protein harboring this mutation was 19.5% compared with the normal control, but was increased up to 31.6% by the addition of pyridoxal 5-prime-phosphate in vitro. RFLP analysis with BspHI restriction revealed that the mother was a carrier of the mutation. <a href="#29" class="mim-tip-reference" title="Harigae, H., Furuyama, K., Kimura, A., Neriishi, K., Tahara, N., Kondo, M., Hayashi, N., Yamamoto, M., Sassa, S., Sasaki, T. <strong>A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia.</strong> Brit. J. Haemat. 106: 175-177, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10444183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10444183</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01479.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10444183">Harigae et al. (1999)</a> stated that 23 different mutations encompassing exons of the catalytic region of the ALAS2 gene had been described. The 1754A-G mutation was the only one located in exon 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10444183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852307;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=rs137852307" 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=rs137852307" 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=RCV000011223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011223</a>
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<p><a href="#12" class="mim-tip-reference" title="Cazzola, M., May, A., Bergamaschi, G., Cerani, P., Rosti, V., Bishop, D. F. <strong>Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females.</strong> Blood 96: 4363-4365, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110715</a>]" pmid="11110715">Cazzola et al. (2000)</a> identified a missense mutation in the ALAS2 gene in a 72-year-old woman whose hemoglobin level had been normal at the age of 36 years. She later presented at age 64 with breathlessness and fatigue and was found to have severe microcytic anemia. Because of microcytosis and pyridoxine responsiveness, the patient was thought to have late-onset X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>). She was found to be heterozygous for a G-to-A transition at nucleotide 1236 in exon 9, which resulted in a cys395-to-tyr amino acid substitution. She expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation but had normal hemoglobin levels and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the same ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia in the grandson as well as in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, <a href="#2" class="mim-tip-reference" title="Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W. <strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong> EMBO J. 24: 3166-3177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16121195">Astner et al. (2005)</a> determined that replacement of cys395 by the significantly larger tyrosine would adversely affect PLP binding. Correspondingly, the activity of this mutant enzyme could be rescued by higher concentrations of PLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852308;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=rs137852308" 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=rs137852308" 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=RCV000011224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011224</a>
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<p>In 2 affected males from a family with pyridoxine-responsive X-linked sideroblastic anemia (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#30" class="mim-tip-reference" title="Hurford, M. T., Marshall-Taylor, C., Vicki, S. L., Zhou, J. Z., Silverman, L. M., Rezuke, W. N., Altman, A., Tsongalis, G. J. <strong>A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia.</strong> Clin. Chim. Acta 321: 49-53, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12031592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12031592</a>] [<a href="https://doi.org/10.1016/s0009-8981(02)00095-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12031592">Hurford et al. (2002)</a> identified an asp159-to-tyr (D159Y) mutation in the ALAS2 gene. Another mutation at codon 159 has also been reported (D159N; <a href="#0012">301300.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12031592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852308;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=rs137852308" 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=rs137852308" 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=RCV000011225" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011225" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011225</a>
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<p>In an 81-year-old man in whom X-linked sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>) was precipitated by maintenance hemodialysis therapy, <a href="#26" class="mim-tip-reference" title="Furuyama, K., Harigae, H., Kinoshita, C., Shimada, T., Miyaoka, K., Kanda, C., Maruyama, Y., Shibahara, S., Sassa, S. <strong>Late-onset X-linked sideroblastic anemia following hemodialysis.</strong> Blood 101: 4623-4624, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531813</a>] [<a href="https://doi.org/10.1182/blood-2002-09-2804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531813">Furuyama et al. (2003)</a> identified heterozygosity for a 527G-A transition in exon 5 of the ALAS2 gene, resulting in an asp159-to-asn (D159N) mutation. Other members of the family could not be studied. The D159N mutation did not appear to be a polymorphism, as it was not found in 44 ALAS2 control alleles from the Japanese population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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ALAS2, -206C-G, PROMOTER
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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> rs140772352 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs140772352;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/rs140772352?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=rs140772352" 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=rs140772352" 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=RCV000011226 OR RCV001520731 OR RCV004751209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011226, RCV001520731, RCV004751209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011226...</a>
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<p>In a 32-year-old woman with sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>) of mild phenotype and moderately late onset, <a href="#5" class="mim-tip-reference" title="Bekri, S., May, A., Cotter, P. D., Al-Sabah, A. I., Guo, X., Masters, G. S., Bishop, D. F. <strong>A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia.</strong> Blood 102: 698-704, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12663458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12663458</a>] [<a href="https://doi.org/10.1182/blood-2002-06-1623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12663458">Bekri et al. (2003)</a> found a promoter mutation in the ALAS2 gene, a C-to-G transversion at nucleotide -206 from the transcription start site, as defined by primer extension. The same mutation was found in her affected son but not in any of her unaffected relatives. Pyridoxine therapy had no effect in the proband, but in her affected son engendered a modest increase in hemoglobin concentration and a 4-fold reduction in ferritin iron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12663458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852309;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=rs137852309" 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=rs137852309" 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=RCV000011227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011227</a>
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<p>In a male with hereditary sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#23" class="mim-tip-reference" title="Edgar, A. J., Wickramasinghe, S. N. <strong>Hereditary sideroblastic anaemia due to a mutation in exon 10 of the erythroid 5-aminolaevulinate synthase gene.</strong> Brit. J. Haemat. 100: 389-392, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488633</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1998.00569.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9488633">Edgar and Wickramasinghe (1998)</a> identified a 1622C-G transversion in exon 10 of the ALAS2 gene, resulting in a his524-to-asp (H524D) substitution. This histidine is highly conserved. The proband's mother and sister were heterozygous carriers of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9488633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387906472 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906472;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=rs387906472" 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=rs387906472" 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=RCV000011228 OR RCV001851788 OR RCV004584322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011228, RCV001851788, RCV004584322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011228...</a>
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<p>In 6 families with X-linked erythropoietic protoporphyria (XLEPP; <a href="/entry/300752">300752</a>), <a href="#35" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> identified a 4-bp deletion in exon 11 of the ALAS2 gene (1706_1709delAGTG). The mutation occurred on 5 different haplotypes, suggesting that it had arisen on at least 5 separate occasions. Expression studies in E. coli showed that this deletion resulted in a marked increase in ALAS2 activity and that some of the 5-aminolevulinate (ALA) that is produced is further metabolized to porphyrin. These findings of a gain of function strongly suggested that protoporphyrin and its zinc chelate accumulate in XLEPP because the rate of ALA formation is increased to such an extent that insertion of iron into protoporphyrin by ferrochelatase (FECH; <a href="/entry/612386">612386</a>) becomes rate limiting for heme synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> identified the c.1706delAGTG mutation in 2 unrelated girls, of Swiss and French origin, respectively, with XLEPP. Both had severe photosensitivity by 3 years of age, iron deficiency, and increased erythrocyte zinc-protoporphyrin. One patient had gallstones. The mother of the French girl had a milder form of the disorder and was found to be germline and somatic mosaic for the mutation. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity consistent with a gain of function. There was no evidence of a founder effect, suggesting that the mutation may represent a hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387906473 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906473;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=rs387906473" 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=rs387906473" 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=RCV000011229" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011229" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011229</a>
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<p>In 2 families from southwest England with X-linked erythropoietic protoporphyria (XLEPP; <a href="/entry/300752">300752</a>), <a href="#35" class="mim-tip-reference" title="Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. <strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong> Am. J. Hum. Genet. 83: 408-414, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760763">Whatley et al. (2008)</a> identified a 2-bp deletion in exon 11 of ALAS2 (1699_1700delAT). This deletion occurred on the same haplotype in both families. This mutation when expressed in E. coli resulted in a gain of function of ALAS2 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852310;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=rs137852310" 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=rs137852310" 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=RCV000011230" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011230" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011230</a>
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<p>In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#16" class="mim-tip-reference" title="Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. <strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong> Blood 93: 1757-1769, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10029606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10029606</a>]" pmid="10029606">Cotter et al. (1999)</a> identified a 647T-C transition in exon 5 of the ALAS2 gene, resulting in a tyr199-to-his (Y199H) substitution. The mother was heterozygous for the mutation, which was not found in any other family member or in any of 100 normal alleles. The proband had severe and early iron loading coinherited hereditary hemochromatosis with a homozygous C232Y mutation in the HFE gene (<a href="/entry/235200#0001">235200.0001</a>). Reversal of the iron overload in this patient resulted in higher hemoglobin concentrations during pyridoxine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10029606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs137852311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852311;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/rs137852311?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=rs137852311" 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=rs137852311" 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=RCV000011231 OR RCV000254885 OR RCV004730841" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011231, RCV000254885, RCV004730841" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011231...</a>
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<p>In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; <a href="/entry/300751">300751</a>), <a href="#16" class="mim-tip-reference" title="Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. <strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong> Blood 93: 1757-1769, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10029606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10029606</a>]" pmid="10029606">Cotter et al. (1999)</a> identified a 1406C-T transition in exon 9 of the ALAS2 gene, resulting in an arg452-to-cys (R452C) substitution. The mutation was not found in any of 100 normal alleles. <a href="#16" class="mim-tip-reference" title="Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. <strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong> Blood 93: 1757-1769, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10029606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10029606</a>]" pmid="10029606">Cotter et al. (1999)</a> stated that the same mutation had been found in another family with XLSA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10029606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514730 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514730;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=rs397514730" 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=rs397514730" 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=RCV000054488" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054488" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054488</a>
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<p>In an Australian girl with X-linked erythropoietic protoporphyria (<a href="/entry/300752">300752</a>), <a href="#22" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> identified a heterozygous c.1642C-T transition in exon 11 of the ALAS2 gene, resulting in a gln548-to-ter (Q548X) substitution. The mutation was not found in 100 control chromosomes or a large control database. The patient had onset in childhood of severe photosensitivity associated with increased liver enzymes, iron deficiency, and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255567 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255567;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=rs879255567" 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=rs879255567" 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=RCV000054489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054489</a>
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<p>In a Dutch girl, whose parents originally came from Afghanistan, with XLDPP (<a href="/entry/300752">300752</a>), <a href="#22" class="mim-tip-reference" title="Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. <strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong> Hum. Molec. Genet. 22: 1280-1288, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23263862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23263862</a>] [<a href="https://doi.org/10.1093/hmg/dds531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23263862">Ducamp et al. (2013)</a> identified a heterozygous 26-bp deletion (c.1651_1677) in exon 11 of the ALAS2 gene, resulting in a frameshift and premature termination (Ser551ProfsTer5). The mutation was not found in 100 control chromosomes or in a large control database. The patient had onset in infancy of severe photosensitivity associated with elevated liver enzymes and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23263862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Aoki1973" class="mim-anchor"></a>
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Aoki, Y., Urata, G., Takaku, F.
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<strong>Delta-aminolevulinic acid synthetase activity in erythroblasts of patients with primary sideroblastic anemia.</strong>
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Astner, I., Schulze, J. O., van den Heuvel, J., Jahn, D., Schubert, W.-D., Heinz, D. W.
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<strong>Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16121195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16121195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16121195[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=16121195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.emboj.7600792" target="_blank">Full Text</a>]
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Astrin, K. H., Bishop, D. F.
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<strong>Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to the X chromosome. (Abstract)</strong>
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Astrin, K. H., Desnick, R. J., Bishop, D. F.
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<strong>Assignment of human delta-aminolevulinate synthase (ALAS) to chromosome 3. (Abstract)</strong>
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Cytogenet. Cell Genet. 46: 573, 1987.
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Bekri, S., May, A., Cotter, P. D., Al-Sabah, A. I., Guo, X., Masters, G. S., Bishop, D. F.
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<strong>A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia.</strong>
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Blood 102: 698-704, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12663458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12663458</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12663458" 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/10.1182/blood-2002-06-1623" target="_blank">Full Text</a>]
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Benoff, S., Bruce, S. A., Skoultchi, A. I.
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<strong>Negative control of hemoglobin production in somatic cell hybrids due to heme deficiency.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/279921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">279921</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=279921" 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/10.1073/pnas.75.9.4354" target="_blank">Full Text</a>]
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Benoff, S., Skoultchi, A. I.
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<strong>X-linked control of hemoglobin production in somatic hybrids of mouse erythroleukemic cells and mouse lymphoma or bone marrow cells.</strong>
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Cell 12: 263-274, 1977.
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[<a href="https://doi.org/10.1016/0092-8674(77)90204-5" target="_blank">Full Text</a>]
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Bishop, D. F., Henderson, A. S., Astrin, K. H.
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<strong>Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347585</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2347585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(90)90542-3" target="_blank">Full Text</a>]
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Blair, H. J., Ho, M., Monaco, A. P., Fisher, S., Craig, I. W., Boyd, Y.
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[<a href="https://doi.org/10.1006/geno.1995.1146" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199806183382515" target="_blank">Full Text</a>]
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Cazzola, M., May, A., Bergamaschi, G., Cerani, P., Rosti, V., Bishop, D. F.
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<strong>Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females.</strong>
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Blood 96: 4363-4365, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>A severe type of hereditary anemia with elliptocytosis: interesting sequence of splenectomy.</strong>
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<strong>Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.</strong>
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[<a href="https://doi.org/10.1073/pnas.89.9.4028" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Cotter, P. D., May, A., Fitzsimons, E. J., Houston, T., Woodcock, B. E., Al-Sabah, A. I., Wong, L., Bishop, D. F.
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<strong>Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.</strong>
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[<a href="https://doi.org/10.1172/JCI118258" target="_blank">Full Text</a>]
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<strong>Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.</strong>
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<strong>X-linked sideroblastic anemia: identification of the mutation in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) in the original family described by Cooley.</strong>
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Blood 84: 3915-3924, 1994.
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Cotter, P. D., Willard, H. F., Gorski, J. L., Bishop, D. F.
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<strong>Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X;autosome translocations.</strong>
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Genomics 13: 211-212, 1992.
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[<a href="https://doi.org/10.1016/0888-7543(92)90223-f" target="_blank">Full Text</a>]
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<strong>Erythroid 5-aminolevulinate synthase is located on the X chromosome.</strong>
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<strong>X-linked pyridoxine-responsive sideroblastic anemia due to a thr388-to-ser substitution in erythroid 5-aminolevulinate synthase.</strong>
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[<a href="https://doi.org/10.1056/NEJM199403103301004" target="_blank">Full Text</a>]
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<strong>Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia.</strong>
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Hum. Molec. Genet. 1: 639-641, 1992.
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[<a href="https://doi.org/10.1093/hmg/1.8.639" target="_blank">Full Text</a>]
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<strong>Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).</strong>
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[<a href="https://doi.org/10.1093/hmg/dds531" target="_blank">Full Text</a>]
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<strong>Hereditary sideroblastic anaemia due to a mutation in exon 10 of the erythroid 5-aminolaevulinate synthase gene.</strong>
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[<a href="https://doi.org/10.1046/j.1365-2141.1998.00569.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.3.1.1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2002-09-2804" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.1998.01050.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2006.07.147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.1999.01479.x" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Hurford2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hurford, M. T., Marshall-Taylor, C., Vicki, S. L., Zhou, J. Z., Silverman, L. M., Rezuke, W. N., Altman, A., Tsongalis, G. J.
|
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<strong>A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia.</strong>
|
|
Clin. Chim. Acta 321: 49-53, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12031592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12031592</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12031592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0009-8981(02)00095-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Prades1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prades, E., Chambon, C., Dailey, T. A., Dailey, H. A., Briere, J., Grandchamp, B.
|
|
<strong>A new mutation of the ALAS2 gene in a large family with X-linked sideroblastic anemia.</strong>
|
|
Hum. Genet. 95: 424-428, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7705839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7705839</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7705839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00208968" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Puck1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Puck, J. M., Willard, H. F.
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<strong>X inactivation in females with X-linked disease.</strong>
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New Eng. J. Med. 338: 325-327, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9445416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9445416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9445416" 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/NEJM199801293380611" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Raskind1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Raskind, W. H., Wijsman, E., Pagon, R. A., Cox, T. C., Bawden, M. J., May, B. K., Bird, T. D.
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<strong>X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.</strong>
|
|
Am. J. Hum. Genet. 48: 335-341, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Surinya1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Surinya, K. H., Cox, T. C., May, B. K.
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<strong>Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene.</strong>
|
|
J. Biol. Chem. 273: 16798-16809, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9642238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9642238</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9642238" 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.273.27.16798" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Whatley2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H.
|
|
<strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong>
|
|
Am. J. Hum. Genet. 83: 408-414, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18760763[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=18760763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.08.003" target="_blank">Full Text</a>]
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</p>
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</div>
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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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<a id="contributors" 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="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Cassandra L. Kniffin - updated : 8/8/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 4/8/2009<br>Cassandra L. Kniffin - updated : 12/3/2008<br>Ada Hamosh - updated : 11/5/2008<br>Carol A. Bocchini - updated : 11/4/2008<br>George E. Tiller - updated : 10/15/2003<br>Victor A. McKusick - updated : 9/15/2003<br>Victor A. McKusick - updated : 2/14/2001<br>Victor A. McKusick - updated : 9/15/2000<br>Victor A. McKusick - updated : 10/5/1999<br>Victor A. McKusick - updated : 4/16/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 6/18/1998<br>Victor A. McKusick - updated : 10/29/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<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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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" 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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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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alopez : 12/11/2017
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</span>
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</div>
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</div>
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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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carol : 03/17/2016<br>carol : 3/16/2016<br>ckniffin : 3/16/2016<br>carol : 8/14/2013<br>ckniffin : 8/8/2013<br>mgross : 4/9/2009<br>terry : 4/8/2009<br>carol : 12/3/2008<br>ckniffin : 12/3/2008<br>alopez : 12/2/2008<br>alopez : 12/2/2008<br>terry : 11/5/2008<br>carol : 11/4/2008<br>carol : 3/17/2004<br>cwells : 10/15/2003<br>tkritzer : 9/23/2003<br>tkritzer : 9/17/2003<br>tkritzer : 9/15/2003<br>carol : 11/24/2001<br>cwells : 2/19/2001<br>terry : 2/14/2001<br>terry : 9/15/2000<br>carol : 10/13/1999<br>terry : 10/5/1999<br>carol : 4/19/1999<br>terry : 4/16/1999<br>carol : 4/2/1999<br>carol : 2/15/1999<br>terry : 2/2/1999<br>carol : 10/23/1998<br>alopez : 6/26/1998<br>terry : 6/25/1998<br>carol : 6/19/1998<br>terry : 6/18/1998<br>mark : 11/3/1997<br>terry : 10/29/1997<br>carol : 6/20/1997<br>mark : 1/25/1996<br>terry : 1/22/1996<br>terry : 10/27/1995<br>mark : 8/25/1995<br>carol : 2/17/1995<br>mimadm : 2/27/1994<br>carol : 11/30/1992<br>carol : 6/3/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 301300
|
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</span>
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</h3>
|
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
|
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|
|
DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2
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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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<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>
|
|
<span class="mim-font">
|
|
ALAS, ERYTHROID; ALASE<br />
|
|
5-AMINOLEVULINATE SYNTHASE, ERYTHROID-SPECIFIC
|
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: ALAS2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1197360001, 48983004;
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<strong>ICD10CM:</strong> D64.0;
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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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<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: Xp11.21
|
|
|
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Genomic coordinates <span class="small">(GRCh38)</span> : X:55,009,055-55,030,977 </span>
|
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</em>
|
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</strong>
|
|
<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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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<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>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
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<tr>
|
|
<td rowspan="2">
|
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<span class="mim-font">
|
|
Xp11.21
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Anemia, sideroblastic, 1
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300751
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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|
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Protoporphyria, erythropoietic, X-linked
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300752
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</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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<br />
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<span class="mim-text-font">
|
|
<p>Delta-aminolevulinate synthase (ALAS; EC 2.3.1.27) catalyzes the first committed step of heme biosynthesis, which is the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5-phosphate (PLP)-dependent manner (Astner et al., 2005). Two forms of ALAS exist in humans: a housekeeping form encoded by the ALAS1 gene (125290), and an erythroid tissue-specific form encoded by the ALAS2 gene (Bishop et al., 1990). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Astrin and Bishop (1989) isolated the ALAS2 gene from an erythroid human fetal liver library. ALAS2 appeared to be expressed only in erythroid cells.</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>Surinya et al. (1998) determined that the ALAS2 gene spans about 35 kb and contains 11 exons. An erythroid-specific enhancer in intron 8 contains GATA and CACCC boxes that are conserved in mouse and canine Alas2. </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>Benoff and Skoultchi (1977) presented 3 lines of evidence that a locus on the X chromosome in the mouse controls hemoglobin synthesis. Following Ohno's law, one would expect the same locus to exist in man. </p><p>Benoff et al. (1978) identified in the mouse an X-linked locus that inhibits hemoglobin production by inhibiting inducible heme biosynthesis, probably at the step catalyzed by delta-aminolevulinic acid synthetase. Close linkage to the Xg locus was excluded by Elves et al. (1966). </p><p>Astrin et al. (1987) mapped the ALAS1 gene to chromosome 3, excluding it as a candidate gene for X-linked hypochromic anemia. Later, however, Astrin and Bishop (1989) isolated a second ALAS gene, ALAS2, and by Southern blot analysis of DNAs from somatic cell hybrids, assigned it to the X chromosome. Also see Bishop et al. (1990). </p><p>By Southern analysis of a mouse/human hybrid cell panel and by in situ hybridization, Cox et al. (1990) mapped the ALAS2 gene to chromosome Xp21-q21, with the most likely location being on band Xp11.2. </p><p>By analysis of DNA from hybrid clones containing translocations in the region Xp11.21-q21.3, Cotter et al. (1992) achieved finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. They localized the ALAS2 gene to subregion Xp11.21. Cox et al. (1992) identified a highly polymorphic marker, a compound dinucleotide repeat, within intron 7 of the ALAS2 gene and used it to confirm the localization of ALAS2 in the multipoint linkage map of the X chromosome. No recombination was observed between ALAS2 and the centromere marker DXZ1. No recombination was found with DXS14. Since Raskind et al. (1991) excluded linkage of DXS14 and X-linked sideroblastic anemia with spinocerebellar ataxia within 5 to 10 cM, one can probably conclude that there are at least 2 loci on the X chromosome determining sideroblastic anemia. One locus may be located on the proximal portion of Xq. </p><p>In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Alas2 gene relative to others. </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 Function</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>Using a reporter gene assay, Surinya et al. (1998) showed that intron 8 of the ALAS2 gene harbored strong orientation-dependent erythroid-specific enhancer activity. In vitro assays showed that GATA1 (305371) and SP1 (189906) bound the GATA and CACCC boxes within this region, respectively. </p><p>Han et al. (2006) showed that histone deacetylase (HDAC; see 601241) inhibitors increased ALAS2 expression in a human erythroid cell line. Increased ALAS2 expression was concurrent with increased acetylation of histone H4 (see 602822) at the ALAS2 promoter. Histone acetyltransferase p300 (EP300; 602700) bound the ALAS2 promoter, and overexpression of p300 increased promoter reporter expression and endogenous ALAS2 mRNA levels. The GATA1 and SP1 sites at the ALAS2 promoter synergistically contributed to p300-mediated ALAS2 activation. </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">
|
|
<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>Astner et al. (2005) determined the crystal structure of homodimeric Alas from Rhodobacter capsulatus, which shares 49% sequence identity with human ALAS. Mutations in the ALAS gene resulting in X-linked sideroblastic anemia were predicted to obstruct substrate binding, disrupt the dimer interface, or hamper proper folding (see, e.g., 301300.0002-301300.0005). The findings provided explanations for potential responsiveness to pyridoxine treatment in some cases. </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>Sideroblastic Anemia 1, X-Linked</em></strong></p><p>
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|
Aoki et al. (1973) found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia-1 (SIDBA1; 300751), some of whom were males with congenital anemia which in some responded to treatment with vitamin B6. </p><p>In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia, Cotter et al. (1992) identified a mutation in the ALAS2 gene (301300.0001). </p><p>Cotter et al. (1995) described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. She was found to be heterozygous for a point mutation of the ALAS2 gene (301300.0005). The initial diagnosis was myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. There is evidence from other sources that skewed lyonization can be an acquired pattern. In the study of peripheral blood leukocytes by Busque et al. (1996), the incidence of skewing was 1.9% in neonates, 4.5% in women who were 28 to 32 years old, and 22.7% in women who were 60 years of age or older. Cazzola and Bergamaschi (1998) estimated that in 30 to 40% of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90% expression of 1 parental X chromosome. Puck and Willard (1998) reviewed mechanisms for a skewed pattern with a diagram of 3 different mechanisms. </p><p>In each of 4 unrelated males with X-linked sideroblastic anemia, Cotter et al. (1999) identified new mutations: 647T-C, 1283C-T, 1395G-A, and 1406C-T predicting amino acid substitutions tyr199 to his (Y199H; 301300.0017), arg411 to cys (R411C; 301300.0008), arg448 to gln (R448Q), and arg452 to cys (R452C; 301300.0018), respectively. All probands were clinically pyridoxine-responsive. The Y199H mutation was demonstrated to be the first de novo XLSA mutation, having occurred in a gamete of the proband's maternal grandfather. In 18 unrelated XLSA hemizygotes, Cotter et al. (1999) found a significantly higher frequency of coinheritance of the hereditary hemochromatosis HFE mutant allele C282Y (235200.0001) than found in the normal population. One proband with the Y199H mutation with severe and early iron loading was homozygous for C282Y. </p><p>In an 81-year-old man who developed sideroblastic anemia while undergoing hemodialysis, Furuyama et al. (2003) identified heterozygosity for an asp159-to-asn change in the ALAS2 gene (D159N; 301300.0012). </p><p><strong><em>Erythropoietic Protoporphyria, X-Linked</em></strong></p><p>
|
|
In 8 families with X-linked dominant erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified 2 deletion mutations in exon 11 of the ALAS2 gene (301300.0015 and 301300.0016). The mutations were not found in 129 unrelated patients with other forms of erythropoietic protoporphyria or 100 normal chromosomes. The data of Whatley et al. (2008) demonstrated that disruption of the C-terminal region of ALAS2 leads to the production of protoporphyrin in excess of the amount required for hemoglobinization and in quantities sufficient to cause photosensitivity and liver damage, in spite of normal ferrochelatase (FECH; 612386) activity. </p><p>In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. All 4 girls presented in early childhood with severe photosensitivity associated with increased erythrocyte zinc- and metal-free protoporphyrin. Two had elevated liver enzymes, 1 had gallstones, and most had iron deficiency. The mother of 1 child was mildly affected and was shown to be somatic and germline mosaic for the mutation. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the 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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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>20 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">
|
|
<strong>.0001 ANEMIA, SIDEROBLASTIC, 1</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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ALAS2, ILE471ASN
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<br />
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SNP: rs137852299,
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ClinVar: RCV000011214
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1992) identified a T-to-A transition in codon 471 in a highly conserved region of exon 9 of the ALAS gene, resulting in an ile-to-asn substitution. The mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of beta-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs showed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5-prime-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5-prime-phosphate binding site. To identify the mutation, Cotter et al. (1992) amplified and sequenced the 11 exonic coding regions of the ALAS gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
|
ALAS2, THR388SER
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<br />
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SNP: rs137852300,
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|
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ClinVar: RCV000011215
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|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected males and 1 carrier female in a kindred with X-linked pyridoxine-responsive sideroblastic anemia-1 (SIDBA1; 300751), Cox et al. (1994) demonstrated a cytosine-to-guanine change at nucleotide 1215 in exon 8. This change resulted in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wildtype. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appeared to introduce a conformational change at the active site of the enzyme. </p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that thr388 is part of the PLP recognition pattern. Substitution of threonine by serine would allow for higher rotational freedom of serine, significantly reducing the affinity of ALAS for PLP. Correspondingly, patients would respond favorably to pyridoxine treatment. </p>
|
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</span>
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</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
ALAS2, PHE165LEU
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<br />
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SNP: rs137852301,
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|
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ClinVar: RCV000011216, RCV001857329
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the original family with X-linked sideroblastic anemia-1 (SIDBA1; 300751) described by Cooley (1945), Cotter et al. (1994) found that the ALAS2 gene harbored an A-to-C transversion in exon 5, predicted to result in the substitution of leucine for phenylalanine at residue 165 (F165L). The mutation occurred in the first highly conserved domain of the ALAS2 catalytic core shared by all species. </p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that phe165 structurally stabilizes the neighboring arg163, required for sCoA carboxylate group recognition, through hydrophobic interactions. Replacing phe165 by leucine destabilizes arg163, reducing the specificity of sCoA binding. As PLP binding is not affected by the mutation, response to pyridoxine treatment was predicted to be marginal. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
ALAS2, GLY291SER
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|
|
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<br />
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|
|
SNP: rs137852302,
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|
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ClinVar: RCV000011217
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large kindred with a pyridoxine-sensitive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Prades et al. (1995) found a G-to-A transition at nucleotide 871 of the coding sequence (exon 7) of the ALAS2 gene. This resulted in a gly291-to-ser amino acid substitution. The glycine is conserved through evolution in ALAS proteins deduced from DNA sequences of a large number of different organisms. With a PCR assay, they demonstrated the mutation in 3 affected males and 2 female carriers, whereas the carrier status was excluded in 8 females at risk. Early detection of the mutant allele in family members may be important for the prevention of anemia in males and of ion overload both in affected males and carrier females. </p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of gly291 by ser would decrease the affinity of ALAS for sCoA. Furthermore, gly291 is 1 helical turn away from his285, which is involved in PLP binding. As a result, this mutation may be counteracted by increasing levels of PLP. </p>
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|
</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ALAS2, LYS299GLN
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|
|
<br />
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|
|
|
SNP: rs137852303,
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|
|
|
|
|
|
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ClinVar: RCV000011218
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|
|
|
|
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</span>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Cotter et al. (1995) reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; 300751) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A-to-C transversion in exon 7 (K299Q) of the ALAS2 gene in the man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; 301300.0006). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. Cotter et al. (1995) suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate. </p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect. </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>.0006 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
|
|
ALAS2, ALA172THR
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|
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<br />
|
|
|
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SNP: rs137852304,
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|
|
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gnomAD: rs137852304,
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|
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ClinVar: RCV000011219, RCV001729346
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>See 301300.0005 and Cotter et al. (1995). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
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|
|
ALAS2, ASP190VAL
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<br />
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|
|
SNP: rs28935484,
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|
|
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|
|
ClinVar: RCV003322588
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|
|
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1997) identified a 621A-T transversion in the ALAS2 gene that led to an asp190-to-val amino acid substitution. The anemia was refractory to pyridoxine treatment. </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>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 ANEMIA, SIDEROBLASTIC, 1</strong>
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|
</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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ALAS2, ARG411CYS
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|
<br />
|
|
|
|
SNP: rs137852305,
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|
|
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|
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|
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ClinVar: RCV000011221, RCV003555997
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Japanese patient with pyridoxine-responsive X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1998) identified an arg411-to-cys missense mutation of the ALAS2 gene. The normal and mutant cDNAs were expressed in E. coli, and mutant enzyme protein was found to have 12% and 25% ALAS activity when incubated in the absence and presence of pyridoxal 5-prime-phosphate, respectively, compared with that of the wildtype enzyme. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
ALAS2, SER568GLY
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<br />
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SNP: rs137852306,
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ClinVar: RCV000011222
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In an 18-year-old Japanese male with sideroblastic anemia-1 (SIDBA1; 300751), Harigae et al. (1999) identified a 1754A-G missense mutation in exon 11 of the ALAS2 gene, resulting in a ser568-to-gly amino acid substitution. ALAS activity in bone marrow cells of the patient was reduced to 53.3% of the normal control. Consistent with this finding, activity of a bacterially expressed ALAS2 mutant protein harboring this mutation was 19.5% compared with the normal control, but was increased up to 31.6% by the addition of pyridoxal 5-prime-phosphate in vitro. RFLP analysis with BspHI restriction revealed that the mother was a carrier of the mutation. Harigae et al. (1999) stated that 23 different mutations encompassing exons of the catalytic region of the ALAS2 gene had been described. The 1754A-G mutation was the only one located in exon 11. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
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|
ALAS2, CYS395TYR
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<br />
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|
|
SNP: rs137852307,
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|
|
ClinVar: RCV000011223
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|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Cazzola et al. (2000) identified a missense mutation in the ALAS2 gene in a 72-year-old woman whose hemoglobin level had been normal at the age of 36 years. She later presented at age 64 with breathlessness and fatigue and was found to have severe microcytic anemia. Because of microcytosis and pyridoxine responsiveness, the patient was thought to have late-onset X-linked sideroblastic anemia-1 (SIDBA1; 300751). She was found to be heterozygous for a G-to-A transition at nucleotide 1236 in exon 9, which resulted in a cys395-to-tyr amino acid substitution. She expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation but had normal hemoglobin levels and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the same ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia in the grandson as well as in the proband. </p><p>By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of cys395 by the significantly larger tyrosine would adversely affect PLP binding. Correspondingly, the activity of this mutant enzyme could be rescued by higher concentrations of PLP. </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>.0011 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, ASP159TYR
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|
|
<br />
|
|
|
|
SNP: rs137852308,
|
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|
|
|
|
ClinVar: RCV000011224
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected males from a family with pyridoxine-responsive X-linked sideroblastic anemia (SIDBA1; 300751), Hurford et al. (2002) identified an asp159-to-tyr (D159Y) mutation in the ALAS2 gene. Another mutation at codon 159 has also been reported (D159N; 301300.0012). </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>.0012 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, ASP159ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852308,
|
|
|
|
|
|
|
|
ClinVar: RCV000011225
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 81-year-old man in whom X-linked sideroblastic anemia-1 (SIDBA1; 300751) was precipitated by maintenance hemodialysis therapy, Furuyama et al. (2003) identified heterozygosity for a 527G-A transition in exon 5 of the ALAS2 gene, resulting in an asp159-to-asn (D159N) mutation. Other members of the family could not be studied. The D159N mutation did not appear to be a polymorphism, as it was not found in 44 ALAS2 control alleles from the Japanese population. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, -206C-G, PROMOTER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs140772352,
|
|
|
|
|
|
gnomAD: rs140772352,
|
|
|
|
|
|
ClinVar: RCV000011226, RCV001520731, RCV004751209
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old woman with sideroblastic anemia-1 (SIDBA1; 300751) of mild phenotype and moderately late onset, Bekri et al. (2003) found a promoter mutation in the ALAS2 gene, a C-to-G transversion at nucleotide -206 from the transcription start site, as defined by primer extension. The same mutation was found in her affected son but not in any of her unaffected relatives. Pyridoxine therapy had no effect in the proband, but in her affected son engendered a modest increase in hemoglobin concentration and a 4-fold reduction in ferritin iron. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, HIS524ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137852309,
|
|
|
|
|
|
|
|
ClinVar: RCV000011227
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with hereditary sideroblastic anemia-1 (SIDBA1; 300751), Edgar and Wickramasinghe (1998) identified a 1622C-G transversion in exon 10 of the ALAS2 gene, resulting in a his524-to-asp (H524D) substitution. This histidine is highly conserved. The proband's mother and sister were heterozygous carriers of the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, 4-BP DEL, 1706AGTG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906472,
|
|
|
|
|
|
|
|
ClinVar: RCV000011228, RCV001851788, RCV004584322
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 families with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 4-bp deletion in exon 11 of the ALAS2 gene (1706_1709delAGTG). The mutation occurred on 5 different haplotypes, suggesting that it had arisen on at least 5 separate occasions. Expression studies in E. coli showed that this deletion resulted in a marked increase in ALAS2 activity and that some of the 5-aminolevulinate (ALA) that is produced is further metabolized to porphyrin. These findings of a gain of function strongly suggested that protoporphyrin and its zinc chelate accumulate in XLEPP because the rate of ALA formation is increased to such an extent that insertion of iron into protoporphyrin by ferrochelatase (FECH; 612386) becomes rate limiting for heme synthesis. </p><p>Ducamp et al. (2013) identified the c.1706delAGTG mutation in 2 unrelated girls, of Swiss and French origin, respectively, with XLEPP. Both had severe photosensitivity by 3 years of age, iron deficiency, and increased erythrocyte zinc-protoporphyrin. One patient had gallstones. The mother of the French girl had a milder form of the disorder and was found to be germline and somatic mosaic for the mutation. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity consistent with a gain of function. There was no evidence of a founder effect, suggesting that the mutation may represent a hotspot. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, 2-BP DEL, 1699AT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906473,
|
|
|
|
|
|
|
|
ClinVar: RCV000011229
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families from southwest England with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 2-bp deletion in exon 11 of ALAS2 (1699_1700delAT). This deletion occurred on the same haplotype in both families. This mutation when expressed in E. coli resulted in a gain of function of ALAS2 activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, TYR199HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852310,
|
|
|
|
|
|
|
|
ClinVar: RCV000011230
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 647T-C transition in exon 5 of the ALAS2 gene, resulting in a tyr199-to-his (Y199H) substitution. The mother was heterozygous for the mutation, which was not found in any other family member or in any of 100 normal alleles. The proband had severe and early iron loading coinherited hereditary hemochromatosis with a homozygous C232Y mutation in the HFE gene (235200.0001). Reversal of the iron overload in this patient resulted in higher hemoglobin concentrations during pyridoxine supplementation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ANEMIA, SIDEROBLASTIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, ARG452CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852311,
|
|
|
|
|
|
gnomAD: rs137852311,
|
|
|
|
|
|
ClinVar: RCV000011231, RCV000254885, RCV004730841
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 1406C-T transition in exon 9 of the ALAS2 gene, resulting in an arg452-to-cys (R452C) substitution. The mutation was not found in any of 100 normal alleles. Cotter et al. (1999) stated that the same mutation had been found in another family with XLSA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, GLN548TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514730,
|
|
|
|
|
|
|
|
ClinVar: RCV000054488
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Australian girl with X-linked erythropoietic protoporphyria (300752), Ducamp et al. (2013) identified a heterozygous c.1642C-T transition in exon 11 of the ALAS2 gene, resulting in a gln548-to-ter (Q548X) substitution. The mutation was not found in 100 control chromosomes or a large control database. The patient had onset in childhood of severe photosensitivity associated with increased liver enzymes, iron deficiency, and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALAS2, 26-BP DEL, NT1651
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879255567,
|
|
|
|
|
|
|
|
ClinVar: RCV000054489
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Dutch girl, whose parents originally came from Afghanistan, with XLDPP (300752), Ducamp et al. (2013) identified a heterozygous 26-bp deletion (c.1651_1677) in exon 11 of the ALAS2 gene, resulting in a frameshift and premature termination (Ser551ProfsTer5). The mutation was not found in 100 control chromosomes or in a large control database. The patient had onset in infancy of severe photosensitivity associated with elevated liver enzymes and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H.
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<strong>C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.</strong>
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Am. J. Hum. Genet. 83: 408-414, 2008.
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[PubMed: 18760763]
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.08.003]
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Cassandra L. Kniffin - updated : 8/8/2013<br>Patricia A. Hartz - updated : 4/8/2009<br>Cassandra L. Kniffin - updated : 12/3/2008<br>Ada Hamosh - updated : 11/5/2008<br>Carol A. Bocchini - updated : 11/4/2008<br>George E. Tiller - updated : 10/15/2003<br>Victor A. McKusick - updated : 9/15/2003<br>Victor A. McKusick - updated : 2/14/2001<br>Victor A. McKusick - updated : 9/15/2000<br>Victor A. McKusick - updated : 10/5/1999<br>Victor A. McKusick - updated : 4/16/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 6/18/1998<br>Victor A. McKusick - updated : 10/29/1997
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Victor A. McKusick : 6/4/1986
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