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Entry
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- *606953 - UDP-GALACTOSE-4-EPIMERASE; GALE
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- OMIM
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<p>
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<span class="h4">*606953</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#geneFunction">Gene Function</a>
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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="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606953">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000117308;t=ENST00000617979" 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=2582" 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=606953" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</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=ENSG00000117308;t=ENST00000617979" 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_000403,NM_001008216,NM_001127621" 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_001008216" 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=606953" 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 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="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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<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=06092&isoform_id=06092_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/GALE" 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/1119217,2947219,12654859,34194613,56118217,56237023,68056598,77819933,77819935,119615489,119615490,119615491,119615492,119615493,119615494,119615495,119615496,119615497,119615498,119615499,189067311,189083684,193787078,308219130,312031657" 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/Q14376" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2582" 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=ENSG00000117308;t=ENST00000617979" 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=GALE" 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=GALE" 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+2582" 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/GALE" 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:2582" 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/2582" 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=chr1&hgg_gene=ENST00000617979.5&hgg_start=23795599&hgg_end=23800754&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4116" 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/gale" 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=606953[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=606953[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/ENSG00000117308" 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.gwascentral.org/search?q=GALE" 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=GALE" 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=GALE&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/PA28531" 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:4116" 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/FBgn0035147.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:1921496" 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/GALE#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:1921496" 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/2582/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=2582" 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://wormbase.org/db/gene/gene?name=WBGene00008132;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060421-6479" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:2582" 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=GALE&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> 8849004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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606953
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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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UDP-GALACTOSE-4-EPIMERASE; GALE
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
GALACTOSE EPIMERASE
|
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</span>
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</h4>
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</div>
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</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GALE" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GALE</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/279?start=-3&limit=10&highlight=279">1p36.11</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:23795599-23800754&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'})">1:23,795,599-23,800,754</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=230350,620776" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/279?start=-3&limit=10&highlight=279">
|
|
1p36.11
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Galactose epimerase deficiency
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/230350"> 230350 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Thrombocytopenia 13, syndromic
|
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|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/620776"> 620776 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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<p>The GALE gene encodes UDP-galactose-4-prime-epimerase (<a href="https://enzyme.expasy.org/EC/5.1.3.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 5.1.3.2</a>), which catalyzes the interconversion of UDP-galactose and UDP-glucose, important for galactose metabolism, and the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine, important for protein glycosylation (<a href="#14" class="mim-tip-reference" title="Piller, F., Hanlon, M. H., Hill, R. L. <strong>Co-purification and characterization of UDP-glucose 4-epimerase and UDP-N-acetylglucosamine 4-epimerase from porcine submaxillary glands.</strong> J. Biol. Chem. 258: 10774-10778, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6885800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6885800</a>]" pmid="6885800">Piller et al., 1983</a>; summary by <a href="#17" class="mim-tip-reference" title="Seo, A., Gulsuner, S., Pierce, S., Ben-Harosh, M., Shalev, H., Walsh, T., Krasnov, T., Dgany, O., Doulatov, S., Tamary, H., Shimamura, A., King, M. C. <strong>Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).</strong> Hum. Molec. Genet. 28: 133-142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30247636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30247636</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30247636[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/10.1093/hmg/ddy334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30247636">Seo et al., 2019</a> and <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al., 2023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6885800+30247636+36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Daude, N., Gallaher, T. K., Zeschnigk, M., Starzinski-Powitz, A., Petry, K. G., Haworth, I. S., Reichardt, J. K. V. <strong>Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4-prime-epimerase.</strong> Biochem. Molec. Med. 56: 1-7, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8593531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8593531</a>] [<a href="https://doi.org/10.1006/bmme.1995.1048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8593531">Daude et al. (1995)</a> reported the cloning, characterization, and mapping of a full-length cDNA encoding human GALE. The cDNA encodes a predicted protein of 348 amino acids with a molecular mass of 38,266 Da. The human enzyme is similar to that of rat (87% identity), Kluyveromyces lactis (53%), and E. coli (51%); this similarity allowed <a href="#4" class="mim-tip-reference" title="Daude, N., Gallaher, T. K., Zeschnigk, M., Starzinski-Powitz, A., Petry, K. G., Haworth, I. S., Reichardt, J. K. V. <strong>Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4-prime-epimerase.</strong> Biochem. Molec. Med. 56: 1-7, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8593531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8593531</a>] [<a href="https://doi.org/10.1006/bmme.1995.1048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8593531">Daude et al. (1995)</a> to build a homology model based on the bacterial crystal structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8593531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a> found that GALE is poorly expressed in CD34+ hematopoietic progenitor cells, but is increased during megakaryocyte differentiation. GALE expression was reduced in released platelet-like particles. GALE localized to the endoplasmic reticulum in megakaryocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The galactose epimerase enzyme catalyzes 2 distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. This has been shown by purification of the bifunctional enzyme (<a href="#14" class="mim-tip-reference" title="Piller, F., Hanlon, M. H., Hill, R. L. <strong>Co-purification and characterization of UDP-glucose 4-epimerase and UDP-N-acetylglucosamine 4-epimerase from porcine submaxillary glands.</strong> J. Biol. Chem. 258: 10774-10778, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6885800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6885800</a>]" pmid="6885800">Piller et al., 1983</a>) and by simultaneous loss of both activities in a Chinese hamster ovary cell line (<a href="#8" class="mim-tip-reference" title="Kingsley, D. M., Kozarsky, K. F., Hobbie, L., Krieger, M. <strong>Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-Gal/UDP-GalNAc 4-epimerase deficient mutant.</strong> Cell 44: 749-759, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3948246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3948246</a>] [<a href="https://doi.org/10.1016/0092-8674(86)90841-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3948246">Kingsley et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6885800+3948246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 knockout analysis, <a href="#3" class="mim-tip-reference" title="Broussard, A., Florwick, A., Desbiens, C., Nischan, N., Robertson, C., Guan, Z., Kohler, J. J., Wells, L., Boyce, M. <strong>Human UDP-galactose 4'-epimerase (GALE) is required for cell-surface glycome structure and function.</strong> J. Biol. Chem. 295: 1225-1239, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31819007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31819007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31819007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.RA119.009271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31819007">Broussard et al. (2020)</a> demonstrated that human GALE was required to maintain normal nucleotide sugar levels in nutrient-replete human cells in the absence or presence of supplementary galactose. GALE was also required for glycoprotein and glycolipid biosynthesis. Further analysis demonstrated that GALE was required to support the biosynthesis of sialylated N-glycans on FAS (<a href="/entry/134637">134637</a>) and other surface proteins and that loss of GALE function dysregulated glycoprotein receptor signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31819007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> characterized the entire coding sequence of the GALE gene, which contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By study of human-mouse somatic cell hybrids, <a href="#9" class="mim-tip-reference" title="Lin, M. S., Oizumi, J., Ng, W. G., Alfi, O. S., Donnell, G. N. <strong>Assignment of UDP-gal-4-epimerase gene locus to chromosome 1 in man. (Abstract)</strong> Am. J. Hum. Genet. 30: 132 only, 1978."None>Lin et al. (1978)</a> showed that the gene encoding uridine diphosphate galactose-4-epimerase is on chromosome 1. <a href="#10" class="mim-tip-reference" title="Lin, M. S., Oizumi, J., Ng, W. G., Alfi, O. S., Donnell, G. N. <strong>Regional mapping of the gene for human UDPGal 4-epimerase on chromosome 1 in mouse-human hybrids.</strong> Cytogenet. Cell Genet. 24: 217-223, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/509992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">509992</a>] [<a href="https://doi.org/10.1159/000131383" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="509992">Lin et al. (1979)</a> narrowed the assignment to 1pter-p32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=509992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 04/05/2024."None>Stumpf (2024)</a> mapped the GALE gene to chromosome 1p36.11 based on an alignment of the GALE sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC001273" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC001273</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Galactosemia III</em></strong></p><p>
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In a patient with galactosemia III (GALAC3; <a href="/entry/230350">230350</a>), or galactose epimerase deficiency, <a href="#1" class="mim-tip-reference" title="Alano, A., Almashanu, S., Chinsky, J. M., Costeas, P., Blitzer, M. G., Wulfsberg, E. A., Cowan, T. M. <strong>Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.</strong> J. Inherit. Metab. Dis. 21: 341-350, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700591</a>] [<a href="https://doi.org/10.1023/a:1005342306080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700591">Alano et al. (1998)</a> identified compound heterozygous mutations in the GALE gene (N34S, <a href="#0002">606953.0002</a>; L183P, <a href="#0001">606953.0001</a>). The same patient was reported by <a href="#15" class="mim-tip-reference" title="Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L. <strong>Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.</strong> Am. J. Hum. Genet. 61: 590-598, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326324</a>] [<a href="https://doi.org/10.1086/515517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326324">Quimby et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326324+9700591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> screened for mutations in galactose epimerase-deficient individuals and identified 5 mutations in the GALE gene. The patients were either homozygous or compound heterozygous for the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Syndromic Thrombocytopenia 13</em></strong></p><p>
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In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>), <a href="#17" class="mim-tip-reference" title="Seo, A., Gulsuner, S., Pierce, S., Ben-Harosh, M., Shalev, H., Walsh, T., Krasnov, T., Dgany, O., Doulatov, S., Tamary, H., Shimamura, A., King, M. C. <strong>Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).</strong> Hum. Molec. Genet. 28: 133-142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30247636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30247636</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30247636[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/10.1093/hmg/ddy334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30247636">Seo et al. (2019)</a> identified a homozygous missense mutation in the GALE gene (R51W; <a href="#0009">606953.0009</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). The melting point of the R51W mutant was lower than controls, indicating thermal instability. Knockdown of GALE in CD34+ hematopoietic progenitor cells slowed the proliferation of megakaryocyte precursors, and the colonies that formed were larger than controls. These findings suggested that loss of GALE results in defective megakaryocyte differentiation. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30247636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2-year-old Hispanic boy with THC13, <a href="#5" class="mim-tip-reference" title="Febres-Aldana, C. A., Pelaez, L., Wright, M. S., Maher, O. M., Febres-Aldana, A. J., Sasaki, J., Jayakar, P., Jayakar, A., Diaz-Barbosa, M., Janvier, M., Totapally, B., Salyakina, D., Galvez-Silva, J. R. <strong>A case of UDP-galactose 4-prime-epimerase deficiency associated with dyshematopoiesis and atrioventricular valve malformations: an exceptional clinical phenotype explained by altered N-glycosylation with relative preservation of the Leloir pathway.</strong> Molec. Syndromol. 11: 320-329, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33510604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33510604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33510604[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/10.1159/000511343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33510604">Febres-Aldana et al. (2020)</a> identified compound heterozygous missense mutations in the GALE gene: R51W and G237D (<a href="#0010">606953.0010</a>). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33510604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 19-year-old Hispanic woman with THC13, <a href="#13" class="mim-tip-reference" title="Markovitz, R., Owen, N., Satter, L. F., Kirk, S., Mahoney, D. H., Bertuch, A. A., Scaglia, F. <strong>Expansion of the clinical phenotype of GALE deficiency.</strong> Am. J. Med. Genet. 185A: 3118-3121, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34159722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34159722</a>] [<a href="https://doi.org/10.1002/ajmg.a.62384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34159722">Markovitz et al. (2021)</a> identified a homozygous T150M mutation in the GALE gene (<a href="#0011">606953.0011</a>). The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34159722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients from 2 unrelated families with THC13, <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a> identified compound heterozygous mutations in the GALE gene (<a href="#0011">606953.0011</a>-<a href="#0014">606953.0014</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. Patient peripheral blood progenitor cells showed normal megakaryocyte differentiation, although there was a 60 to 80% reduction in GALE expression in mature megakaryocytes and impaired formation of proplatelets with abnormal morphology and altered distribution of actin (see <a href="/entry/102630">102630</a>) and filamin A (<a href="/entry/300017">300017</a>). Analysis of patient platelets showed decreased GALE levels and enzymatic activity, decreased glycosylation patterns, and increased apoptosis compared to controls. Patient platelets had reduced aggregation in response to stimulation associated with a sharp reduction in glycosylation and membrane expression of GP1BA (<a href="/entry/606672">606672</a>) and ITGB1 (<a href="/entry/135630">135630</a>), which were retained abnormally in the endoplasmic reticulum. VWF (<a href="/entry/613160">613160</a>) expression was also decreased on patient megakaryocytes compared to controls. ITGA2B (<a href="/entry/607759">607759</a>)/ITGB3 (<a href="/entry/173470">173470</a>) expression and function were preserved, as was the thrombopoietin (<a href="/entry/600044">600044</a>) receptor (MPL; <a href="/entry/159530">159530</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Wohlers, T. M., Christacos, N. C., Harreman, M. T., Fridovich-Keil, J. L. <strong>Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.</strong> Am. J. Hum. Genet. 64: 462-470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973283</a>] [<a href="https://doi.org/10.1086/302263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973283">Wohlers et al. (1999)</a> reported a V94M (<a href="#0008">606953.0008</a>) missense mutation in both GALE alleles of a patient with the generalized form of galactose epimerase deficiency. The same mutation was found in homozygous state in 2 other patients with the same clinical picture. The specific activity of the mutant protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-actetylgalactosamine. In contrast, 2 GALE-variant proteins associated with peripheral galactose epimerase deficiency, L313M (<a href="#0006">606953.0006</a>) and D103G (<a href="#0004">606953.0004</a>), demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E (<a href="#0003">606953.0003</a>), demonstrated little if any detectable activity, despite near-normal abundance. Thermal lability and protease sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. Two clinically relevant questions remained unanswered after this study: first, whether epimerase-deficiency galactosemia is clinically a binary disorder or a continuum, and second, whether a genotype-phenotype pattern is emerging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Yeast Studies</em></strong></p><p>
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To enable structural and functional studies of both wildtype and patient-derived alleles of the GALE gene, <a href="#15" class="mim-tip-reference" title="Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L. <strong>Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.</strong> Am. J. Hum. Genet. 61: 590-598, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326324</a>] [<a href="https://doi.org/10.1086/515517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326324">Quimby et al. (1997)</a> developed and applied a null-background yeast expression system for analysis of the human enzyme. They demonstrated that human wildtype GALE sequences phenotypically complemented a yeast gal10 deletion, and they characterized the wildtype human enzyme isolated from these cells. Furthermore, they expressed and characterized 2 mutant alleles, leu183 to pro (L183P; <a href="#0001">606953.0001</a>) and asn34 to ser (N34S; <a href="#0002">606953.0002</a>), derived from a patient with no detectable GALE activity in red blood cells but with approximately 14% activity in cultured lymphoblasts. Analyses of crude extracts of yeast expressing the L183P mutant form of human GALE demonstrated 4% wildtype activity and 6% wildtype abundance. Extracts of yeast expressing the other human mutation, N34S, demonstrated approximately 70% wildtype activity and normal abundance. However, yeast coexpressing both mutations exhibited only approximately 7% wildtype levels of activity, thereby confirming the functional impact of both substitutions and suggesting that dominant-negative interaction may exist between the mutant alleles found in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L. <strong>Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.</strong> Am. J. Hum. Genet. 61: 590-598, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326324</a>] [<a href="https://doi.org/10.1086/515517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326324">Quimby et al. (1997)</a> identified compound heterozygosity for a leu183-to-pro (L183P) and an asn34-to-ser (N34S; <a href="#0002">606953.0002</a>) mutation in the GALE gene in a 5-year-old male with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>) born to a Caucasian mother and a Pakistani father. Newborn screening at 6 and 9 days of age showed abnormally elevated galactose sugars but normal GALT (<a href="/entry/606999">606999</a>) activity. The child remained clinically well on a lactose-containing diet, with no hepatomegaly, liver disease, vomiting, or acidosis. At approximately 1 year of age he began experiencing delays in gross motor development, and at age 5 years he exhibited mild to moderate mental retardation with global delays in language and cognitive abilities, although he was otherwise healthy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908046;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/rs121908046?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=rs121908046" 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=rs121908046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003861 OR RCV000723966 OR RCV001582463 OR RCV005016235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003861, RCV000723966, RCV001582463, RCV005016235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003861...</a>
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</span>
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<span class="mim-text-font">
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<p>For discussion of the asn34-to-ser (N34S) mutation in the GALE gene that was found in compound heterozygous state in a patient with galactose epimerase deficiency (<a href="/entry/230350">230350</a>) by <a href="#15" class="mim-tip-reference" title="Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L. <strong>Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.</strong> Am. J. Hum. Genet. 61: 590-598, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326324</a>] [<a href="https://doi.org/10.1086/515517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326324">Quimby et al. (1997)</a>, see <a href="#0001">606953.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 GALACTOSEMIA III</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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<div style="float: left;">
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GALE, GLY90GLU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28940882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940882;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=rs28940882" 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=rs28940882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003862" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003862" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003862</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Asian patient with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>), <a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> identified on 1 GALE allele a GGG-to-GAG transition that changed codon 90 from glycine to glutamic acid (G90E). The other allele was not characterized. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<a id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 GALACTOSEMIA III</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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<div style="float: left;">
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GALE, ASP103GLY
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940883 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940883;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/rs28940883?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=rs28940883" 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=rs28940883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003863</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>On both alleles of the GALE gene in an Asian patient with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>), <a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> found a GAT-to-GGT transition in the GALE gene that changed an aspartic acid at codon 103 to glycine (D103G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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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="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 GALACTOSEMIA III</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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<div style="float: left;">
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GALE, LYS257ARG
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940884 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940884;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/rs28940884?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=rs28940884" 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=rs28940884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003864 OR RCV000592410 OR RCV000609606 OR RCV004752683" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003864, RCV000592410, RCV000609606, RCV004752683" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003864...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an African American patient with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>), <a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> identified a homozygous AAG-to-AGG transition in the GALE gene that changed codon 257 from lysine to arginine (K257R). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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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="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 GALACTOSEMIA III</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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<div style="float: left;">
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GALE, LEU313MET
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs3180383 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3180383;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=rs3180383" 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=rs3180383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003865" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003865" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003865</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Asian patient with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>), <a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> found a CTG-to-ATG transversion in the GALE gene that changed codon 313 from leucine to methionine (L313M). The patient was heterozygous for this mutation. The other mutation was not identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 GALACTOSEMIA III</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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<div style="float: left;">
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GALE, GLY319GLU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940885 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940885;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/rs28940885?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=rs28940885" 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=rs28940885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003866 OR RCV000078697 OR RCV003904802" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003866, RCV000078697, RCV003904802" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003866...</a>
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</span>
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</div>
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<div>
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<p><a href="#11" class="mim-tip-reference" title="Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J. <strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong> Molec. Genet. Metab. 63: 26-30, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9538513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9538513</a>] [<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9538513">Maceratesi et al. (1998)</a> found that 1 African American patient with galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>) was heterozygous for a GGG-to-GAG transition in the GALE gene that changed codon 319 from glycine to glutamic acid (G319E). The other mutation was not identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9538513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908047;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/rs121908047?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=rs121908047" 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=rs121908047" 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=RCV000003867 OR RCV000020292 OR RCV000727367 OR RCV002512728 OR RCV005003325" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003867, RCV000020292, RCV000727367, RCV002512728, RCV005003325" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003867...</a>
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<p>In what they claimed to be the first case of molecularly characterized severe galactose epimerase deficiency (GALAC3; <a href="/entry/230350">230350</a>), <a href="#21" class="mim-tip-reference" title="Wohlers, T. M., Christacos, N. C., Harreman, M. T., Fridovich-Keil, J. L. <strong>Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.</strong> Am. J. Hum. Genet. 64: 462-470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973283</a>] [<a href="https://doi.org/10.1086/302263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973283">Wohlers et al. (1999)</a> identified a homozygous val94-to-met (V94M) missense mutation in the GALE gene. The patient was the product of a consanguineous marriage and had been described by <a href="#7" class="mim-tip-reference" title="Holton, J. B., Gillett, M. G., MacFaul, R., Young, R. <strong>Galactosaemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency.</strong> Arch. Dis. Child. 56: 885-887, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7305435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7305435</a>] [<a href="https://doi.org/10.1136/adc.56.11.885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7305435">Holton et al. (1981)</a> and <a href="#6" class="mim-tip-reference" title="Henderson, M. J., Holton, J. B., MacFaul, R. <strong>Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.</strong> J. Inherit. Metab. Dis. 6: 17-20, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6408303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6408303</a>] [<a href="https://doi.org/10.1007/BF02391187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6408303">Henderson et al. (1983)</a>. She presented at age 5 days with symptoms of classic galactosemia (<a href="/entry/230400">230400</a>), including vomiting, hypotonia, jaundice, galactosuria, and hepatomegaly. Enzyme activities of galactose-1 phosphate uridylyltransferase (<a href="/entry/606999">606999</a>) and galactokinase (<a href="/entry/604313">604313</a>) were within normal limits. GALE activity, however, was deficient both in erythrocytes and in cultured skin fibroblasts. At age 19 months, the child remained hypotonic, with an enlarged spleen and developmental delay, despite a galactose-restricted diet (<a href="#6" class="mim-tip-reference" title="Henderson, M. J., Holton, J. B., MacFaul, R. <strong>Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.</strong> J. Inherit. Metab. Dis. 6: 17-20, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6408303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6408303</a>] [<a href="https://doi.org/10.1007/BF02391187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6408303">Henderson et al., 1983</a>). Later in life, she was noted to have nerve deafness and moderate learning difficulties, but there was no evidence of ovarian dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6408303+9973283+7305435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The V94M protein is impaired relative to the wildtype enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences of the mutation on the 3-dimensional architecture of the enzyme, <a href="#20" class="mim-tip-reference" title="Thoden, J. B., Wohlers, T. M., Fridovich-Keil, J. L., Holden, H. M. <strong>Molecular basis for severe epimerase deficiency galactosemia: x-ray structure of the human V94M-substituted UDP-galactose 4-epimerase.</strong> J. Biol. Chem. 276: 20617-20623, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279193</a>] [<a href="https://doi.org/10.1074/jbc.M101304200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279193">Thoden et al. (2001)</a> solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. They found that the net effect of the V94M substitution is an opening up of the ala93-to-glu96 surface loop, which allows free rotation of the sugars into nonproductive binding modes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs780517804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs780517804;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/rs780517804?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=rs780517804" 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=rs780517804" 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=RCV001265572 OR RCV002307717 OR RCV003994248 OR RCV005014318" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001265572, RCV002307717, RCV003994248, RCV005014318" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001265572...</a>
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<p>In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>), <a href="#17" class="mim-tip-reference" title="Seo, A., Gulsuner, S., Pierce, S., Ben-Harosh, M., Shalev, H., Walsh, T., Krasnov, T., Dgany, O., Doulatov, S., Tamary, H., Shimamura, A., King, M. C. <strong>Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).</strong> Hum. Molec. Genet. 28: 133-142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30247636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30247636</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30247636[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/10.1093/hmg/ddy334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30247636">Seo et al. (2019)</a> identified a homozygous c.151C-T transition (c.151C-T, NM_001127621) in the GALE gene, resulting in an arg51-to-trp (R51W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). Of note, the mutant protein was able to rescue yeast growth upon galactose challenge in gal10-null yeast (gal10 is the homologous gene to GALE and catalyzes the interconversion of UDP-galactose and UDP-glucose, but not the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine). Accordingly, the patients did not have clinical signs of galactosemia. The melting point of the R51W mutant was lower than controls, indicating thermal instability. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on normal glycosylation and hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30247636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For discussion of the R51W mutation in the GALE gene that was found in compound heterozygous state in a 2-year-old Hispanic boy with THC13 by <a href="#5" class="mim-tip-reference" title="Febres-Aldana, C. A., Pelaez, L., Wright, M. S., Maher, O. M., Febres-Aldana, A. J., Sasaki, J., Jayakar, P., Jayakar, A., Diaz-Barbosa, M., Janvier, M., Totapally, B., Salyakina, D., Galvez-Silva, J. R. <strong>A case of UDP-galactose 4-prime-epimerase deficiency associated with dyshematopoiesis and atrioventricular valve malformations: an exceptional clinical phenotype explained by altered N-glycosylation with relative preservation of the Leloir pathway.</strong> Molec. Syndromol. 11: 320-329, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33510604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33510604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33510604[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/10.1159/000511343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33510604">Febres-Aldana et al. (2020)</a>, see <a href="#0010">606953.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33510604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000732602 OR RCV001260494 OR RCV003994101 OR RCV005056489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000732602, RCV001260494, RCV003994101, RCV005056489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000732602...</a>
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<p>In a 2-year-old Hispanic boy with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>), <a href="#5" class="mim-tip-reference" title="Febres-Aldana, C. A., Pelaez, L., Wright, M. S., Maher, O. M., Febres-Aldana, A. J., Sasaki, J., Jayakar, P., Jayakar, A., Diaz-Barbosa, M., Janvier, M., Totapally, B., Salyakina, D., Galvez-Silva, J. R. <strong>A case of UDP-galactose 4-prime-epimerase deficiency associated with dyshematopoiesis and atrioventricular valve malformations: an exceptional clinical phenotype explained by altered N-glycosylation with relative preservation of the Leloir pathway.</strong> Molec. Syndromol. 11: 320-329, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33510604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33510604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33510604[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/10.1159/000511343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33510604">Febres-Aldana et al. (2020)</a> identified compound heterozygous missense mutations in the GALE gene: a c.710G-A transition, resulting in a gly237-to-asp (G237D) substitution at a conserved residue, and R51W (<a href="#0009">606953.0009</a>). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD. GALE activity in patient red blood cells was decreased compared to controls. The patient had pancytopenia, mitral and tricuspid valve malformations, and pyloric stenosis, but did not have signs of classic galactosemia. The authors postulated that GALE activity in this patient was sufficient to prevent toxic accumulation of galactose, but may be insufficient to compensate for increased demand of UDP-glcNAc/USP-galNAc substrates in cells with higher demand for these glycosylation precursors. Since normal hematopoiesis and genes involved in atrioventricular valve morphogenesis require proper N-glycosylation for adequate functionality, a deficit in N-glycosylation could explain the patient's phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33510604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs765353795 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765353795;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/rs765353795?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=rs765353795" 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=rs765353795" 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=RCV001331200 OR RCV003991510" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001331200, RCV003991510" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001331200...</a>
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<p>In a 19-year-old Hispanic woman, born of consanguineous parents, with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>), <a href="#13" class="mim-tip-reference" title="Markovitz, R., Owen, N., Satter, L. F., Kirk, S., Mahoney, D. H., Bertuch, A. A., Scaglia, F. <strong>Expansion of the clinical phenotype of GALE deficiency.</strong> Am. J. Med. Genet. 185A: 3118-3121, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34159722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34159722</a>] [<a href="https://doi.org/10.1002/ajmg.a.62384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34159722">Markovitz et al. (2021)</a> identified a homozygous c.449C-T transition (c.449C-T, NM_000403.3) in exon 5 in the GALE gene, resulting in a thr150-to-met (T150M) substitution. The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34159722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 adult sibs (family A) with THC13, <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a> identified compound heterozygous mutations in the GALE gene: T150M and a 4-bp insertion (c.230_231insTGTT; <a href="#0012">606953.0012</a>) in exon 3, predicted to result in a frameshift and premature termination (Lys78ValfsTer32). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 THROMBOCYTOPENIA 13, SYNDROMIC</strong>
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<p>For discussion of the 4-bp insertion (c.230_231insTGTT, NM_001127621.2) in exon 3 of the GALE gene, predicted to result in a frameshift and premature termination (Lys78ValfsTer32), that was found in compound heterozygous state in 2 sibs (family A) with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>) by <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a>, see <a href="#0011">606953.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs778887800 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs778887800;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/rs778887800?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=rs778887800" 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=rs778887800" 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=RCV000732601 OR RCV001054710 OR RCV003991507 OR RCV004702382" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000732601, RCV001054710, RCV003991507, RCV004702382" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000732601...</a>
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<p>In a 38-year-old man (family B) with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>), <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a> identified compound heterozygous mutations in the GALE gene: a c.382G-A transition (c.382G-A, NM_001127621.2), resulting in a val128-to-met (V128M) substitution, and a c.668T-C transition in exon 7, resulting in a leu223-to-pro substitution (L223P; <a href="#0014">606953.0014</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs1457875051 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1457875051;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/rs1457875051?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=rs1457875051" 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=rs1457875051" 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=RCV001921713 OR RCV003991512 OR RCV004699558 OR RCV005016867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001921713, RCV003991512, RCV004699558, RCV005016867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001921713...</a>
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<p>For discussion of the c.668T-C transition (c.668T-C, NM_001127621.2) in exon 7 of the GALE gene, resulting in a leu223-to-pro (L223P) substitution that was found in compound heterozygous state in a patient with syndromic thrombocytopenia-13 (THC13; <a href="/entry/620776">620776</a>) by <a href="#12" class="mim-tip-reference" title="Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M. <strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong> Blood 141: 406-421, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36395340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36395340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36395340[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/10.1182/blood.2022016995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36395340">Marin-Quilez et al. (2023)</a>, see <a href="#0013">606953.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36395340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Benn1979" class="mim-tip-reference" title="Benn, P. A., Shows, T. B., D'Ancona, G. G., Croce, C. M., Orkwiszewski, K. G., Mellman, W. J. <strong>Assignment of a gene for uridine diphosphate galactose-4-epimerase to human chromosome 1 by somatic cell hybridization, with evidence for a regional assignment to 1pter-1p21.</strong> Cytogenet. Cell Genet. 24: 138-142, 1979.">Benn et al. (1979)</a>; <a href="#Schulpis1993" class="mim-tip-reference" title="Schulpis, K. H., Papaconstantinou, E. D., Koidou, A., Michelakakis, H., Tzamouranis, J., Patsouras, A., Shin, Y. <strong>UDP galactose-4-epimerase deficiency in a 5.5-year-old girl with a unilateral cataract.</strong> J. Inherit. Metab. Dis. 16: 903-904, 1993.">Schulpis et al. (1993)</a>; <a href="#Tamary2003" class="mim-tip-reference" title="Tamary, H., Yaniv, I., Stein, J., Dgany, O., Shalev, Z., Shechter, T., Resnitzky, P., Shaft, D., Zoldan, M., Kornreich, L., Levy, R., Cohen, A., Moser, R. A., Kapelushnik, J., Shalev, H. <strong>A clinical and molecular study of a Bedouin family with dysmegakaryopoiesis, mild anemia, and neutropenia cured by bone marrow transplantation.</strong> Europ. J. Haemat. 71: 196-203, 2003.">Tamary et al. (2003)</a>
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[<a href="https://doi.org/10.1023/a:1005342306080" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000131369" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.RA119.009271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bmme.1995.1048" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02391187" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/mgme.1997.2645" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood.2022016995" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30247636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30247636</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30247636[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=30247636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy334" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Stumpf2024" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 04/05/2024.
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</p>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Tamary2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tamary, H., Yaniv, I., Stein, J., Dgany, O., Shalev, Z., Shechter, T., Resnitzky, P., Shaft, D., Zoldan, M., Kornreich, L., Levy, R., Cohen, A., Moser, R. A., Kapelushnik, J., Shalev, H.
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<strong>A clinical and molecular study of a Bedouin family with dysmegakaryopoiesis, mild anemia, and neutropenia cured by bone marrow transplantation.</strong>
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Europ. J. Haemat. 71: 196-203, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12930321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12930321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12930321" 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/10.1034/j.1600-0609.2003.00126.x" target="_blank">Full Text</a>]
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Thoden2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thoden, J. B., Wohlers, T. M., Fridovich-Keil, J. L., Holden, H. M.
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<strong>Molecular basis for severe epimerase deficiency galactosemia: x-ray structure of the human V94M-substituted UDP-galactose 4-epimerase.</strong>
|
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J. Biol. Chem. 276: 20617-20623, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279193</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279193" 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.M101304200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Wohlers1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wohlers, T. M., Christacos, N. C., Harreman, M. T., Fridovich-Keil, J. L.
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<strong>Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.</strong>
|
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Am. J. Hum. Genet. 64: 462-470, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302263" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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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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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/19/2024
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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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Anne M. Stumpf - updated : 04/05/2024<br>Cassandra L. Kniffin - updated : 04/03/2024
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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="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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Cassandra L. Kniffin : 5/21/2002
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</span>
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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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carol : 08/19/2024
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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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alopez : 04/05/2024<br>ckniffin : 04/03/2024<br>carol : 04/28/2020<br>carol : 04/27/2020<br>mcolton : 08/18/2015<br>wwang : 7/27/2009<br>terry : 11/16/2006<br>ckniffin : 6/10/2002<br>carol : 6/7/2002<br>carol : 5/29/2002<br>ckniffin : 5/29/2002
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</span>
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</div>
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<div class="container visible-print-block">
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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> 606953
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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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UDP-GALACTOSE-4-EPIMERASE; GALE
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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>
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<span class="mim-font">
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GALACTOSE EPIMERASE
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</h4>
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<div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GALE</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> 8849004;
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</span>
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</p>
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<div>
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<br />
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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: 1p36.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:23,795,599-23,800,754 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<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-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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1p36.11
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</span>
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</td>
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<td>
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<span class="mim-font">
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Galactose epimerase deficiency
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</span>
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</td>
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<td>
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<span class="mim-font">
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230350
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Thrombocytopenia 13, syndromic
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</span>
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</td>
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<td>
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<span class="mim-font">
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620776
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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</tr>
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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The GALE gene encodes UDP-galactose-4-prime-epimerase (EC 5.1.3.2), which catalyzes the interconversion of UDP-galactose and UDP-glucose, important for galactose metabolism, and the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine, important for protein glycosylation (Piller et al., 1983; summary by Seo et al., 2019 and Marin-Quilez et al., 2023). </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>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Daude et al. (1995) reported the cloning, characterization, and mapping of a full-length cDNA encoding human GALE. The cDNA encodes a predicted protein of 348 amino acids with a molecular mass of 38,266 Da. The human enzyme is similar to that of rat (87% identity), Kluyveromyces lactis (53%), and E. coli (51%); this similarity allowed Daude et al. (1995) to build a homology model based on the bacterial crystal structure. </p><p>Marin-Quilez et al. (2023) found that GALE is poorly expressed in CD34+ hematopoietic progenitor cells, but is increased during megakaryocyte differentiation. GALE expression was reduced in released platelet-like particles. GALE localized to the endoplasmic reticulum in megakaryocytes. </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">
|
|
<p>The galactose epimerase enzyme catalyzes 2 distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. This has been shown by purification of the bifunctional enzyme (Piller et al., 1983) and by simultaneous loss of both activities in a Chinese hamster ovary cell line (Kingsley et al., 1986). </p><p>By knockout analysis, Broussard et al. (2020) demonstrated that human GALE was required to maintain normal nucleotide sugar levels in nutrient-replete human cells in the absence or presence of supplementary galactose. GALE was also required for glycoprotein and glycolipid biosynthesis. Further analysis demonstrated that GALE was required to support the biosynthesis of sialylated N-glycans on FAS (134637) and other surface proteins and that loss of GALE function dysregulated glycoprotein receptor signaling. </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>Maceratesi et al. (1998) characterized the entire coding sequence of the GALE gene, which contains 11 exons. </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>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By study of human-mouse somatic cell hybrids, Lin et al. (1978) showed that the gene encoding uridine diphosphate galactose-4-epimerase is on chromosome 1. Lin et al. (1979) narrowed the assignment to 1pter-p32. </p><p>Stumpf (2024) mapped the GALE gene to chromosome 1p36.11 based on an alignment of the GALE sequence (GenBank BC001273) with the genomic sequence (GRCh38).</p>
|
|
</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>Molecular Genetics</strong>
|
|
</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Galactosemia III</em></strong></p><p>
|
|
In a patient with galactosemia III (GALAC3; 230350), or galactose epimerase deficiency, Alano et al. (1998) identified compound heterozygous mutations in the GALE gene (N34S, 606953.0002; L183P, 606953.0001). The same patient was reported by Quimby et al. (1997). </p><p>Maceratesi et al. (1998) screened for mutations in galactose epimerase-deficient individuals and identified 5 mutations in the GALE gene. The patients were either homozygous or compound heterozygous for the mutations. </p><p><strong><em>Syndromic Thrombocytopenia 13</em></strong></p><p>
|
|
In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; 620776), Seo et al. (2019) identified a homozygous missense mutation in the GALE gene (R51W; 606953.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). The melting point of the R51W mutant was lower than controls, indicating thermal instability. Knockdown of GALE in CD34+ hematopoietic progenitor cells slowed the proliferation of megakaryocyte precursors, and the colonies that formed were larger than controls. These findings suggested that loss of GALE results in defective megakaryocyte differentiation. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on hematopoiesis. </p><p>In a 2-year-old Hispanic boy with THC13, Febres-Aldana et al. (2020) identified compound heterozygous missense mutations in the GALE gene: R51W and G237D (606953.0010). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD. </p><p>In a 19-year-old Hispanic woman with THC13, Markovitz et al. (2021) identified a homozygous T150M mutation in the GALE gene (606953.0011). The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc. </p><p>In 3 patients from 2 unrelated families with THC13, Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene (606953.0011-606953.0014). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. Patient peripheral blood progenitor cells showed normal megakaryocyte differentiation, although there was a 60 to 80% reduction in GALE expression in mature megakaryocytes and impaired formation of proplatelets with abnormal morphology and altered distribution of actin (see 102630) and filamin A (300017). Analysis of patient platelets showed decreased GALE levels and enzymatic activity, decreased glycosylation patterns, and increased apoptosis compared to controls. Patient platelets had reduced aggregation in response to stimulation associated with a sharp reduction in glycosylation and membrane expression of GP1BA (606672) and ITGB1 (135630), which were retained abnormally in the endoplasmic reticulum. VWF (613160) expression was also decreased on patient megakaryocytes compared to controls. ITGA2B (607759)/ITGB3 (173470) expression and function were preserved, as was the thrombopoietin (600044) receptor (MPL; 159530). </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>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Wohlers et al. (1999) reported a V94M (606953.0008) missense mutation in both GALE alleles of a patient with the generalized form of galactose epimerase deficiency. The same mutation was found in homozygous state in 2 other patients with the same clinical picture. The specific activity of the mutant protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-actetylgalactosamine. In contrast, 2 GALE-variant proteins associated with peripheral galactose epimerase deficiency, L313M (606953.0006) and D103G (606953.0004), demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E (606953.0003), demonstrated little if any detectable activity, despite near-normal abundance. Thermal lability and protease sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. Two clinically relevant questions remained unanswered after this study: first, whether epimerase-deficiency galactosemia is clinically a binary disorder or a continuum, and second, whether a genotype-phenotype pattern is emerging. </p><p><strong><em>Yeast Studies</em></strong></p><p>
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To enable structural and functional studies of both wildtype and patient-derived alleles of the GALE gene, Quimby et al. (1997) developed and applied a null-background yeast expression system for analysis of the human enzyme. They demonstrated that human wildtype GALE sequences phenotypically complemented a yeast gal10 deletion, and they characterized the wildtype human enzyme isolated from these cells. Furthermore, they expressed and characterized 2 mutant alleles, leu183 to pro (L183P; 606953.0001) and asn34 to ser (N34S; 606953.0002), derived from a patient with no detectable GALE activity in red blood cells but with approximately 14% activity in cultured lymphoblasts. Analyses of crude extracts of yeast expressing the L183P mutant form of human GALE demonstrated 4% wildtype activity and 6% wildtype abundance. Extracts of yeast expressing the other human mutation, N34S, demonstrated approximately 70% wildtype activity and normal abundance. However, yeast coexpressing both mutations exhibited only approximately 7% wildtype levels of activity, thereby confirming the functional impact of both substitutions and suggesting that dominant-negative interaction may exist between the mutant alleles found in this patient. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 GALACTOSEMIA III</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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GALE, LEU183PRO
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<br />
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SNP: rs121908045,
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gnomAD: rs121908045,
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ClinVar: RCV000003860, RCV005016234
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Quimby et al. (1997) identified compound heterozygosity for a leu183-to-pro (L183P) and an asn34-to-ser (N34S; 606953.0002) mutation in the GALE gene in a 5-year-old male with galactose epimerase deficiency (GALAC3; 230350) born to a Caucasian mother and a Pakistani father. Newborn screening at 6 and 9 days of age showed abnormally elevated galactose sugars but normal GALT (606999) activity. The child remained clinically well on a lactose-containing diet, with no hepatomegaly, liver disease, vomiting, or acidosis. At approximately 1 year of age he began experiencing delays in gross motor development, and at age 5 years he exhibited mild to moderate mental retardation with global delays in language and cognitive abilities, although he was otherwise healthy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 GALACTOSEMIA III</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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GALE, ASN34SER
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<br />
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SNP: rs121908046,
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gnomAD: rs121908046,
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ClinVar: RCV000003861, RCV000723966, RCV001582463, RCV005016235
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the asn34-to-ser (N34S) mutation in the GALE gene that was found in compound heterozygous state in a patient with galactose epimerase deficiency (230350) by Quimby et al. (1997), see 606953.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 GALACTOSEMIA III</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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GALE, GLY90GLU
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<br />
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SNP: rs28940882,
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ClinVar: RCV000003862
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) identified on 1 GALE allele a GGG-to-GAG transition that changed codon 90 from glycine to glutamic acid (G90E). The other allele was not characterized. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 GALACTOSEMIA III</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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GALE, ASP103GLY
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<br />
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SNP: rs28940883,
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gnomAD: rs28940883,
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ClinVar: RCV000003863
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>On both alleles of the GALE gene in an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) found a GAT-to-GGT transition in the GALE gene that changed an aspartic acid at codon 103 to glycine (D103G). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 GALACTOSEMIA III</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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GALE, LYS257ARG
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<br />
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SNP: rs28940884,
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gnomAD: rs28940884,
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ClinVar: RCV000003864, RCV000592410, RCV000609606, RCV004752683
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In an African American patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) identified a homozygous AAG-to-AGG transition in the GALE gene that changed codon 257 from lysine to arginine (K257R). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 GALACTOSEMIA III</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
GALE, LEU313MET
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<br />
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|
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SNP: rs3180383,
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|
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ClinVar: RCV000003865
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) found a CTG-to-ATG transversion in the GALE gene that changed codon 313 from leucine to methionine (L313M). The patient was heterozygous for this mutation. The other mutation was not identified. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 GALACTOSEMIA III</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
GALE, GLY319GLU
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<br />
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|
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SNP: rs28940885,
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|
|
gnomAD: rs28940885,
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|
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ClinVar: RCV000003866, RCV000078697, RCV003904802
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Maceratesi et al. (1998) found that 1 African American patient with galactose epimerase deficiency (GALAC3; 230350) was heterozygous for a GGG-to-GAG transition in the GALE gene that changed codon 319 from glycine to glutamic acid (G319E). The other mutation was not identified. </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>.0008 GALACTOSEMIA III, SEVERE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
GALE, VAL94MET
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<br />
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|
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SNP: rs121908047,
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|
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gnomAD: rs121908047,
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|
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ClinVar: RCV000003867, RCV000020292, RCV000727367, RCV002512728, RCV005003325
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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 what they claimed to be the first case of molecularly characterized severe galactose epimerase deficiency (GALAC3; 230350), Wohlers et al. (1999) identified a homozygous val94-to-met (V94M) missense mutation in the GALE gene. The patient was the product of a consanguineous marriage and had been described by Holton et al. (1981) and Henderson et al. (1983). She presented at age 5 days with symptoms of classic galactosemia (230400), including vomiting, hypotonia, jaundice, galactosuria, and hepatomegaly. Enzyme activities of galactose-1 phosphate uridylyltransferase (606999) and galactokinase (604313) were within normal limits. GALE activity, however, was deficient both in erythrocytes and in cultured skin fibroblasts. At age 19 months, the child remained hypotonic, with an enlarged spleen and developmental delay, despite a galactose-restricted diet (Henderson et al., 1983). Later in life, she was noted to have nerve deafness and moderate learning difficulties, but there was no evidence of ovarian dysfunction. </p><p>The V94M protein is impaired relative to the wildtype enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences of the mutation on the 3-dimensional architecture of the enzyme, Thoden et al. (2001) solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. They found that the net effect of the V94M substitution is an opening up of the ala93-to-glu96 surface loop, which allows free rotation of the sugars into nonproductive binding modes. </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>.0009 THROMBOCYTOPENIA 13, SYNDROMIC</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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GALE, ARG51TRP
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<br />
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SNP: rs780517804,
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gnomAD: rs780517804,
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ClinVar: RCV001265572, RCV002307717, RCV003994248, RCV005014318
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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 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; 620776), Seo et al. (2019) identified a homozygous c.151C-T transition (c.151C-T, NM_001127621) in the GALE gene, resulting in an arg51-to-trp (R51W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). Of note, the mutant protein was able to rescue yeast growth upon galactose challenge in gal10-null yeast (gal10 is the homologous gene to GALE and catalyzes the interconversion of UDP-galactose and UDP-glucose, but not the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine). Accordingly, the patients did not have clinical signs of galactosemia. The melting point of the R51W mutant was lower than controls, indicating thermal instability. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on normal glycosylation and hematopoiesis. </p><p>For discussion of the R51W mutation in the GALE gene that was found in compound heterozygous state in a 2-year-old Hispanic boy with THC13 by Febres-Aldana et al. (2020), see 606953.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0010 THROMBOCYTOPENIA 13, SYNDROMIC</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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GALE, GLY237ASP
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<br />
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SNP: rs756944736,
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gnomAD: rs756944736,
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ClinVar: RCV000732602, RCV001260494, RCV003994101, RCV005056489
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 2-year-old Hispanic boy with syndromic thrombocytopenia-13 (THC13; 620776), Febres-Aldana et al. (2020) identified compound heterozygous missense mutations in the GALE gene: a c.710G-A transition, resulting in a gly237-to-asp (G237D) substitution at a conserved residue, and R51W (606953.0009). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD. GALE activity in patient red blood cells was decreased compared to controls. The patient had pancytopenia, mitral and tricuspid valve malformations, and pyloric stenosis, but did not have signs of classic galactosemia. The authors postulated that GALE activity in this patient was sufficient to prevent toxic accumulation of galactose, but may be insufficient to compensate for increased demand of UDP-glcNAc/USP-galNAc substrates in cells with higher demand for these glycosylation precursors. Since normal hematopoiesis and genes involved in atrioventricular valve morphogenesis require proper N-glycosylation for adequate functionality, a deficit in N-glycosylation could explain the patient's phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 THROMBOCYTOPENIA 13, SYNDROMIC</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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GALE, THR150MET
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<br />
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SNP: rs765353795,
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gnomAD: rs765353795,
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|
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ClinVar: RCV001331200, RCV003991510
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 19-year-old Hispanic woman, born of consanguineous parents, with syndromic thrombocytopenia-13 (THC13; 620776), Markovitz et al. (2021) identified a homozygous c.449C-T transition (c.449C-T, NM_000403.3) in exon 5 in the GALE gene, resulting in a thr150-to-met (T150M) substitution. The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc. </p><p>In 2 adult sibs (family A) with THC13, Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene: T150M and a 4-bp insertion (c.230_231insTGTT; 606953.0012) in exon 3, predicted to result in a frameshift and premature termination (Lys78ValfsTer32). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0012 THROMBOCYTOPENIA 13, SYNDROMIC</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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GALE, 4-BP INS, 230TGTT
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<br />
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ClinVar: RCV003991518
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 4-bp insertion (c.230_231insTGTT, NM_001127621.2) in exon 3 of the GALE gene, predicted to result in a frameshift and premature termination (Lys78ValfsTer32), that was found in compound heterozygous state in 2 sibs (family A) with syndromic thrombocytopenia-13 (THC13; 620776) by Marin-Quilez et al. (2023), see 606953.0011. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0013 THROMBOCYTOPENIA 13, SYNDROMIC</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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GALE, VAL128MET
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<br />
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SNP: rs778887800,
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gnomAD: rs778887800,
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|
|
ClinVar: RCV000732601, RCV001054710, RCV003991507, RCV004702382
|
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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 38-year-old man (family B) with syndromic thrombocytopenia-13 (THC13; 620776), Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene: a c.382G-A transition (c.382G-A, NM_001127621.2), resulting in a val128-to-met (V128M) substitution, and a c.668T-C transition in exon 7, resulting in a leu223-to-pro substitution (L223P; 606953.0014). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. </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>.0014 THROMBOCYTOPENIA 13, SYNDROMIC</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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GALE, LEU223PRO
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<br />
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SNP: rs1457875051,
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gnomAD: rs1457875051,
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|
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ClinVar: RCV001921713, RCV003991512, RCV004699558, RCV005016867
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.668T-C transition (c.668T-C, NM_001127621.2) in exon 7 of the GALE gene, resulting in a leu223-to-pro (L223P) substitution that was found in compound heterozygous state in a patient with syndromic thrombocytopenia-13 (THC13; 620776) by Marin-Quilez et al. (2023), see 606953.0013. </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>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Benn et al. (1979); Schulpis et al. (1993); Tamary et al. (2003)
|
|
</span>
|
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<div>
|
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<br />
|
|
</div>
|
|
</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
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Alano, A., Almashanu, S., Chinsky, J. M., Costeas, P., Blitzer, M. G., Wulfsberg, E. A., Cowan, T. M.
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<strong>Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.</strong>
|
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J. Inherit. Metab. Dis. 21: 341-350, 1998.
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[PubMed: 9700591]
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[Full Text: https://doi.org/10.1023/a:1005342306080]
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</p>
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<li>
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<p class="mim-text-font">
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Benn, P. A., Shows, T. B., D'Ancona, G. G., Croce, C. M., Orkwiszewski, K. G., Mellman, W. J.
|
|
<strong>Assignment of a gene for uridine diphosphate galactose-4-epimerase to human chromosome 1 by somatic cell hybridization, with evidence for a regional assignment to 1pter-1p21.</strong>
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Cytogenet. Cell Genet. 24: 138-142, 1979.
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[PubMed: 477411]
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[Full Text: https://doi.org/10.1159/000131369]
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Broussard, A., Florwick, A., Desbiens, C., Nischan, N., Robertson, C., Guan, Z., Kohler, J. J., Wells, L., Boyce, M.
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<strong>Human UDP-galactose 4'-epimerase (GALE) is required for cell-surface glycome structure and function.</strong>
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J. Biol. Chem. 295: 1225-1239, 2020.
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[Full Text: https://doi.org/10.1074/jbc.RA119.009271]
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Daude, N., Gallaher, T. K., Zeschnigk, M., Starzinski-Powitz, A., Petry, K. G., Haworth, I. S., Reichardt, J. K. V.
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<strong>Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4-prime-epimerase.</strong>
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Biochem. Molec. Med. 56: 1-7, 1995.
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[PubMed: 8593531]
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[Full Text: https://doi.org/10.1006/bmme.1995.1048]
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<p class="mim-text-font">
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Febres-Aldana, C. A., Pelaez, L., Wright, M. S., Maher, O. M., Febres-Aldana, A. J., Sasaki, J., Jayakar, P., Jayakar, A., Diaz-Barbosa, M., Janvier, M., Totapally, B., Salyakina, D., Galvez-Silva, J. R.
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<strong>A case of UDP-galactose 4-prime-epimerase deficiency associated with dyshematopoiesis and atrioventricular valve malformations: an exceptional clinical phenotype explained by altered N-glycosylation with relative preservation of the Leloir pathway.</strong>
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Molec. Syndromol. 11: 320-329, 2020.
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[PubMed: 33510604]
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[Full Text: https://doi.org/10.1159/000511343]
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<p class="mim-text-font">
|
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Henderson, M. J., Holton, J. B., MacFaul, R.
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<strong>Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.</strong>
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J. Inherit. Metab. Dis. 6: 17-20, 1983.
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[PubMed: 6408303]
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[Full Text: https://doi.org/10.1007/BF02391187]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Holton, J. B., Gillett, M. G., MacFaul, R., Young, R.
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<strong>Galactosaemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency.</strong>
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Arch. Dis. Child. 56: 885-887, 1981.
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[PubMed: 7305435]
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[Full Text: https://doi.org/10.1136/adc.56.11.885]
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<p class="mim-text-font">
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Kingsley, D. M., Kozarsky, K. F., Hobbie, L., Krieger, M.
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<strong>Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-Gal/UDP-GalNAc 4-epimerase deficient mutant.</strong>
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Cell 44: 749-759, 1986.
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[PubMed: 3948246]
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[Full Text: https://doi.org/10.1016/0092-8674(86)90841-x]
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<p class="mim-text-font">
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Lin, M. S., Oizumi, J., Ng, W. G., Alfi, O. S., Donnell, G. N.
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<strong>Assignment of UDP-gal-4-epimerase gene locus to chromosome 1 in man. (Abstract)</strong>
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|
Am. J. Hum. Genet. 30: 132 only, 1978.
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<p class="mim-text-font">
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Lin, M. S., Oizumi, J., Ng, W. G., Alfi, O. S., Donnell, G. N.
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<strong>Regional mapping of the gene for human UDPGal 4-epimerase on chromosome 1 in mouse-human hybrids.</strong>
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Cytogenet. Cell Genet. 24: 217-223, 1979.
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[PubMed: 509992]
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[Full Text: https://doi.org/10.1159/000131383]
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</p>
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<li>
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<p class="mim-text-font">
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Maceratesi, P., Daude, N., Dallapiccola, B., Novelli, G., Allen, R., Okano, Y., Reichardt, J.
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<strong>Human UDP-galactose 4-prime epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.</strong>
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Molec. Genet. Metab. 63: 26-30, 1998.
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[PubMed: 9538513]
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[Full Text: https://doi.org/10.1006/mgme.1997.2645]
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</p>
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<li>
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<p class="mim-text-font">
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Marin-Quilez, A., Di Buduo, C. A., Diaz-Ajenjo, L., Abbonante, V., Vuelta, E., Soprano, P. M., Miguel-Garcia, C., Santos-Minguez, S., Serramito-Gomez, I., Ruiz-Sala, P., Penarrubia, M. J., Pardal, E., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Garcia-Tunon, I., Benito, R., Rivera, J., Balduini, A., Bastida, J. M.
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|
<strong>Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.</strong>
|
|
Blood 141: 406-421, 2023.
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[PubMed: 36395340]
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[Full Text: https://doi.org/10.1182/blood.2022016995]
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</p>
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<li>
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<p class="mim-text-font">
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Markovitz, R., Owen, N., Satter, L. F., Kirk, S., Mahoney, D. H., Bertuch, A. A., Scaglia, F.
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<strong>Expansion of the clinical phenotype of GALE deficiency.</strong>
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|
Am. J. Med. Genet. 185A: 3118-3121, 2021.
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[PubMed: 34159722]
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[Full Text: https://doi.org/10.1002/ajmg.a.62384]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Piller, F., Hanlon, M. H., Hill, R. L.
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|
<strong>Co-purification and characterization of UDP-glucose 4-epimerase and UDP-N-acetylglucosamine 4-epimerase from porcine submaxillary glands.</strong>
|
|
J. Biol. Chem. 258: 10774-10778, 1983.
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|
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|
|
[PubMed: 6885800]
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Quimby, B. B., Alano, A., Almashanu, S., DeSandro, A. M., Cowan, T. M., Fridovich-Keil, J. L.
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<strong>Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.</strong>
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Am. J. Hum. Genet. 61: 590-598, 1997.
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|
[PubMed: 9326324]
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|
|
[Full Text: https://doi.org/10.1086/515517]
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Schulpis, K. H., Papaconstantinou, E. D., Koidou, A., Michelakakis, H., Tzamouranis, J., Patsouras, A., Shin, Y.
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<strong>UDP galactose-4-epimerase deficiency in a 5.5-year-old girl with a unilateral cataract.</strong>
|
|
J. Inherit. Metab. Dis. 16: 903-904, 1993.
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|
|
|
|
|
[PubMed: 8295413]
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|
[Full Text: https://doi.org/10.1007/BF00714292]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Seo, A., Gulsuner, S., Pierce, S., Ben-Harosh, M., Shalev, H., Walsh, T., Krasnov, T., Dgany, O., Doulatov, S., Tamary, H., Shimamura, A., King, M. C.
|
|
<strong>Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).</strong>
|
|
Hum. Molec. Genet. 28: 133-142, 2019.
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|
|
|
|
|
[PubMed: 30247636]
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|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddy334]
|
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Stumpf, A. M.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 04/05/2024.
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|
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</p>
|
|
</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Tamary, H., Yaniv, I., Stein, J., Dgany, O., Shalev, Z., Shechter, T., Resnitzky, P., Shaft, D., Zoldan, M., Kornreich, L., Levy, R., Cohen, A., Moser, R. A., Kapelushnik, J., Shalev, H.
|
|
<strong>A clinical and molecular study of a Bedouin family with dysmegakaryopoiesis, mild anemia, and neutropenia cured by bone marrow transplantation.</strong>
|
|
Europ. J. Haemat. 71: 196-203, 2003.
|
|
|
|
|
|
[PubMed: 12930321]
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|
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[Full Text: https://doi.org/10.1034/j.1600-0609.2003.00126.x]
|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Thoden, J. B., Wohlers, T. M., Fridovich-Keil, J. L., Holden, H. M.
|
|
<strong>Molecular basis for severe epimerase deficiency galactosemia: x-ray structure of the human V94M-substituted UDP-galactose 4-epimerase.</strong>
|
|
J. Biol. Chem. 276: 20617-20623, 2001.
|
|
|
|
|
|
[PubMed: 11279193]
|
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|
|
[Full Text: https://doi.org/10.1074/jbc.M101304200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wohlers, T. M., Christacos, N. C., Harreman, M. T., Fridovich-Keil, J. L.
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<strong>Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.</strong>
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Am. J. Hum. Genet. 64: 462-470, 1999.
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[PubMed: 9973283]
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[Full Text: https://doi.org/10.1086/302263]
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Bao Lige - updated : 08/19/2024<br>Anne M. Stumpf - updated : 04/05/2024<br>Cassandra L. Kniffin - updated : 04/03/2024
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Cassandra L. Kniffin : 5/21/2002
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