4870 lines
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Entry
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- *604285 - ALANINE-GLYOXYLATE AMINOTRANSFERASE; AGXT
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- OMIM
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<p>
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<span class="h4">*604285</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="#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="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604285">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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<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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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 class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000172482;t=ENST00000307503" 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=189" 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=604285" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000172482;t=ENST00000307503" 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_000030" 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_000030" 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=604285" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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<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=05048&isoform_id=05048_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/AGXT" 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/28561,36582,134855,178273,219433,239843,4557289,6176530,13560684,62988781,119591627,119591628,125659436,126522481,158258945,189067520,221042198,221042214,221046378,2188955247" 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/P21549" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=189" 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=ENSG00000172482;t=ENST00000307503" 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=AGXT" 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=AGXT" 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+189" 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/AGXT" 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:189" 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/189" 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=chr2&hgg_gene=ENST00000307503.4&hgg_start=240868824&hgg_end=240880500&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:341" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:341" 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/agxt" 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=604285[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=604285[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/ENSG00000172482" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=AGXT" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=AGXT" 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=AGXT" 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=AGXT&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/PA24633" 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:341" 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/FBgn0014031.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:1329033" 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/AGXT#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:1329033" 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/189/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://omia.org/OMIA001672/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=189" 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=WBGene00011767;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-010302-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:189" 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=AGXT&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> 65520001<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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604285
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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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ALANINE-GLYOXYLATE AMINOTRANSFERASE; AGXT
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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AGXT1<br />
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AGT<br />
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SERINE-PYRUVATE AMINOTRANSFERASE; SPT; SPAT
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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=AGXT" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AGXT</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/2/1178?start=-3&limit=10&highlight=1178">2q37.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:240868824-240880500&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'})">2:240,868,824-240,880,500</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</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="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/1178?start=-3&limit=10&highlight=1178">
|
|
2q37.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Hyperoxaluria, primary, type 1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
|
<a href="/entry/259900"> 259900 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</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">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604285" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604285" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>The AGXT gene encodes alanine:glyoxylate aminotransferase (AGT; <a href="https://enzyme.expasy.org/EC/2.6.1.44" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.6.1.44</a>), whose activity is largely confined to peroxisomes in the liver. AGT also shows serine:pyruvate aminotransferase activity (<a href="https://enzyme.expasy.org/EC/2.6.1.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.6.1.51</a>) (<a href="#15" class="mim-tip-reference" title="Noguchi, T., Okuno, E., Takada, Y., Minatogawa, Y., Okai, K., Kido, R. <strong>Characteristics of hepatic alanine-glyoxylate aminotransferase in different mammalian species.</strong> Biochem. J. 169: 113-122, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/629740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">629740</a>] [<a href="https://doi.org/10.1042/bj1690113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="629740">Noguchi et al., 1978</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=629740" 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="#24" class="mim-tip-reference" title="Takada, Y., Kaneko, N., Esumi, H., Purdue, P. E., Danpure, C. J. <strong>Human peroxisomal L-alanine:glyoxylate aminotransferase: evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.</strong> Biochem. J. 268: 517-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2363689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2363689</a>] [<a href="https://doi.org/10.1042/bj2680517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2363689">Takada et al. (1990)</a> isolated clones corresponding to the AGT gene from a human liver cDNA library. The deduced 392-residue protein had a calculated molecular mass of 43 kD. The human peroxisomal AGT showed about 78% amino acid sequence identity with rat mitochondrial AGT. The putative pyridoxal phosphate-binding lysine residue at position 209 is conserved. A comparison of the 5-prime sequences indicated that the N-terminal 22 amino acids of the rat translation product are absent from the human protein. The loss of this mitochondrial targeting sequence (MTS) signal during evolution may partly explain the species differences in intracellular localization of AGT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2363689" 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="#21" class="mim-tip-reference" title="Purdue, P. E., Takada, Y., Danpure, C. J. <strong>Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.</strong> J. Cell Biol. 111: 2341-2351, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1703535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1703535</a>] [<a href="https://doi.org/10.1083/jcb.111.6.2341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1703535">Purdue et al. (1990)</a> isolated a clone encoding human liver-specific peroxisomal AGT, also called AGXT. The nucleotide sequences corresponded to the sequence of the AGT cDNA characterized by <a href="#24" class="mim-tip-reference" title="Takada, Y., Kaneko, N., Esumi, H., Purdue, P. E., Danpure, C. J. <strong>Human peroxisomal L-alanine:glyoxylate aminotransferase: evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.</strong> Biochem. J. 268: 517-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2363689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2363689</a>] [<a href="https://doi.org/10.1042/bj2680517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2363689">Takada et al. (1990)</a>. The results of genomic Southern blotting indicated that the human AGT gene is a probably single copy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1703535+2363689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Cellini, B., Montioli, R., Paiardini, A., Lorenzetto, A., Voltattorni, C. B. <strong>Molecular insight into the synergism between the minor allele of human liver peroxisomal alanine:glyoxylate aminotransferase and the F152I mutation.</strong> J. Biol. Chem. 284: 8349-8358, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19155213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19155213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19155213[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.M808965200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19155213">Cellini et al. (2009)</a> noted that AGT functions as a dimer, and each AGT monomer consists of an N-terminal arm involved in dimer formation, a large catalytic domain containing an active site lys209, and a smaller C-terminal domain. One pyridoxal 5-prime-phosphate (PLP) cofactor binds per subunit and is present in a Schiff base linkage with lys209. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19155213" 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="Purdue, P. E., Takada, Y., Danpure, C. J. <strong>Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.</strong> J. Cell Biol. 111: 2341-2351, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1703535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1703535</a>] [<a href="https://doi.org/10.1083/jcb.111.6.2341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1703535">Purdue et al. (1990)</a> determined that the coding sequence of the AGXT gene spans 10 kb and contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1703535" 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 in situ hybridization and PCR analysis of rodent/human somatic cell hybrids, <a href="#17" class="mim-tip-reference" title="Purdue, P. E., Allsop, J., Isaya, G., Rosenberg, L. E., Danpure, C. J. <strong>Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.</strong> Proc. Nat. Acad. Sci. 88: 10900-10904, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961759</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961759">Purdue et al. (1991)</a> mapped the AGXT gene to chromosome 2q36-q37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1961759" 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="#13" class="mim-tip-reference" title="Mori, M., Oda, T., Nishiyama, K., Serikawa, T., Yamada, J., Ichiyama, A. <strong>A single serine:pyruvate aminotransferase gene on rat chromosome 9q34-q36.</strong> Genomics 13: 686-689, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639396</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90142-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639396">Mori et al. (1992)</a> showed by in situ hybridization that a single gene for this enzyme in the rat, symbolized SPT/AGT, is located on chromosome 9q34-q36. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639396" 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>Primary hyperoxaluria type 1 (<a href="/entry/259900">259900</a>) is an autosomal recessive disorder caused by deficiency of alanine:glyoxylate aminotransferase (AGT), characterized by progressive kidney failure due to renal deposition of calcium oxalate. In about one-third of patients residual enzyme activity is up to 60% of mean normal, but in most of these patients AGT is mistargeted to mitochondria instead of peroxisomes. The mistargeting mutation gly170-to-arg (G170R; <a href="#0013">604285.0013</a>) is the most common mutation among Caucasian patients, with a frequency of 23 to 27%. The G170R mutation always occurs on the background of the minor allele (see <a href="#0002">604285.0002</a>), with which it interacts synergistically (summary by <a href="#4" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rumsby, G. <strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong> Molec. Genet. Metab. 83: 38-46, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15464418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15464418</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15464418">Coulter-Mackie and Rumsby, 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15464418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Danpure, C. J., Jennings, P. R. <strong>Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type I.</strong> FEBS Lett. 201: 20-24, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3709805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3709805</a>] [<a href="https://doi.org/10.1016/0014-5793(86)80563-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3709805">Danpure and Jennings (1986)</a> demonstrated that total AGXT levels were reduced in 2 patients with type I primary hyperoxaluria (<a href="/entry/259900">259900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3709805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with primary hyperoxaluria type I (HP1; <a href="/entry/259900">259900</a>), <a href="#14" class="mim-tip-reference" title="Nishiyama, K., Funai, T., Katafuchi, R., Hattori, F., Onoyama, K., Ichiyama, A. <strong>Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene.</strong> Biochem. Biophys. Res. Commun. 176: 1093-1099, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2039493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2039493</a>] [<a href="https://doi.org/10.1016/0006-291x(91)90396-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2039493">Nishiyama et al. (1991)</a> identified a mutation in the AGXT gene (S205P; <a href="#0001">604285.0001</a>). SPT activity was approximately 1% of that in control liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2039493" 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 intermediary metabolic enzyme AGT contains a pro11-to-leu (P11L; <a href="#0002">604285.0002</a>) polymorphism that decreases its catalytic activity by a factor of 3 and causes a small proportion to be mistargeted from its normal intracellular location in the peroxisomes to the mitochondria. These changes were predicted to have significant effects on the synthesis and excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract (summary by <a href="#10" class="mim-tip-reference" title="Danpure, C. J. <strong>Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease.</strong> Bioessays 19: 317-326, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9136629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9136629</a>] [<a href="https://doi.org/10.1002/bies.950190409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9136629">Danpure, 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9136629" 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 15 unrelated Italian patients with type I primary hyperoxaluria, <a href="#16" class="mim-tip-reference" title="Pirulli, D., Puzzer, D., Ferri, L., Crovella, S., Amoroso, A., Ferrettini, C., Marangella, M., Mazzola, G., Florian, F. <strong>Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine:glyoxylate aminotransferase gene.</strong> Hum. Genet. 104: 523-525, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453743</a>] [<a href="https://doi.org/10.1007/s004390050998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453743">Pirulli et al. (1999)</a> 8 novel mutations in the AGXT gene (see, e.g., G158R, <a href="#0012">604285.0012</a>). The most frequent mutation was G170R (<a href="#0013">604285.0013</a>), accounting for 30% of alleles, followed by G158R, with a 13% frequency. Ten of the 15 patients were homozygotes; in only 1 case were the parents identified as first cousins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453743" 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 mutation update of the AGXT gene, <a href="#27" class="mim-tip-reference" title="Williams, E. L., Acquaviva, C., Amoroso, A., Chevalier, F., Coulter-Mackie, M., Monico, C. G., Giachino, D., Owen, T., Robbiano, A., Salido, E., Waterham, H., Rumsby, G. <strong>Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.</strong> Hum. Mutat. 30: 910-917, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19479957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19479957</a>] [<a href="https://doi.org/10.1002/humu.21021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19479957">Williams et al. (2009)</a> stated that 146 mutations had been identified, with all exons of the AGXT gene represented. The authors identified 50 novel mutations in patients with HP1. There were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19479957" 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="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al. (2013)</a> showed that 3 disease-causing missense mutations, I244T (<a href="#0007">604285.0007</a>), F152I (<a href="#0006">604285.0006</a>), and G41R (<a href="#0005">604285.0005</a>), which occur on the background of the minor allele characterized by the P11L polymorphism, can, like G170R, unmask the cryptic P11L-generated mitochondrial targeting sequence and result in AGT protein being mistargeted to mitochondria. These 4 missense mutations together constitute 40% of HP1 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" 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>Based on the evolution of AGT targeting in mammals, <a href="#10" class="mim-tip-reference" title="Danpure, C. J. <strong>Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease.</strong> Bioessays 19: 317-326, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9136629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9136629</a>] [<a href="https://doi.org/10.1002/bies.950190409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9136629">Danpure (1997)</a> hypothesized that the common P11L polymorphism would be advantageous for individuals who have a meat-rich diet, but disadvantageous for those who do not. If true, the frequency of distribution of P11L in different extant human populations should have been shaped by their dietary history so that it should be more common in populations with predominantly meat-eating ancestral diets than it is in populations in which the ancestral diet was predominantly vegetarian. In a study of frequency of P11L in 11 different human populations with divergent ancestral dietary lifestyles, <a href="#2" class="mim-tip-reference" title="Caldwell, E. F., Mayor, L. R., Thomas, M. G., Danpure, C. J. <strong>Diet and the frequency of the alanine:glyoxylate aminotransferase pro11leu polymorphism in different human populations.</strong> Hum. Genet. 115: 504-509, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15480793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15480793</a>] [<a href="https://doi.org/10.1007/s00439-004-1191-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15480793">Caldwell et al. (2004)</a> found evidence in support of the hypothesis: the highest allelic frequency, 27.9%, was found in the Saami, a population with a very meat-rich ancestral diet; the lowest, 2.3%, was found in Chinese, who were likely to have had a more mixed ancestral diet. The differences in P11L frequency between some populations (particularly Saami vs Chinese) was very high when compared with neutral loci, suggesting that its frequency might have been shaped by dietary selection pressure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15480793+9136629" 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="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al. (2013)</a> stated that the minor allele characterized by the P11L polymorphism occurs in 15 to 20% of European and North American populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" 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="#22" class="mim-tip-reference" title="Salido, E. C., Li, X. M., Lu, Y., Wang, X., Santana, A., Roy-Chowdhury, N., Torres, A., Shapiro, L. J., Roy-Chowdhury, J. <strong>Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer.</strong> Proc. Nat. Acad. Sci. 103: 18249-18254, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110443[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/10.1073/pnas.0607218103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110443">Salido et al. (2006)</a> found that Agt1-null mice grew and developed normally; however they developed hyperoxaluria and crystalluria. About half of the male mice in mixed genetic background developed calcium oxalate urinary stones. Severe nephrocalcinosis and renal failure developed after pharmacologic enhancement of oxalate production. Hepatic expression of human AGT1 by adenoviral vector-mediated gene transfer in Agt1 -/- mice normalized urinary oxalate excretion and prevented oxalate crystalluria. Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expression of transgenic AGT1 was predominantly localized to hepatocellular peroxisomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110443" 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> rs121908520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908520;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/rs121908520?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=rs121908520" 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=rs121908520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#14" class="mim-tip-reference" title="Nishiyama, K., Funai, T., Katafuchi, R., Hattori, F., Onoyama, K., Ichiyama, A. <strong>Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene.</strong> Biochem. Biophys. Res. Commun. 176: 1093-1099, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2039493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2039493</a>] [<a href="https://doi.org/10.1016/0006-291x(91)90396-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2039493">Nishiyama et al. (1991)</a> obtained cDNA clones for serine:pyruvate aminotransferase from a cDNA library constructed from the liver of a patient with primary hyperoxaluria type I (HP1; <a href="/entry/259900">259900</a>) in which the SPT activity was approximately 1% of that in control liver. Genetic analysis identified a 634T-C transition in the AGXT gene, resulting in a ser205-to-pro (S205P) substitution. The T-to-C conversion created a new SmaI site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2039493" 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> rs121908529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908529;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/rs121908529?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=rs121908529" 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=rs121908529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs34116584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34116584;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/rs34116584?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=rs34116584" 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=rs34116584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.</p><p>The pro11-to-leu substitution (P11L) is the primary polymorphism that defines the minor allele of AGXT that occurs with an allele frequency of 15 to 20% in European and North American populations and 50% of patients with primary hyperoxaluria type I (HP1; <a href="/entry/259900">259900</a>). The absence of these polymorphisms defines the major allele. The P11L replacement creates a hidden N-terminal mitochondrial targeting sequence that can be unmasked by additional amino acid substitutions in cis, resulting in disease (summary by <a href="#11" class="mim-tip-reference" title="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rumsby, G. <strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong> Molec. Genet. Metab. 83: 38-46, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15464418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15464418</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15464418">Coulter-Mackie and Rumsby (2004)</a> noted that the P11L substitution results from a 32C-T transition in exon 1 of AGXT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15464418" 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="#21" class="mim-tip-reference" title="Purdue, P. E., Takada, Y., Danpure, C. J. <strong>Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.</strong> J. Cell Biol. 111: 2341-2351, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1703535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1703535</a>] [<a href="https://doi.org/10.1083/jcb.111.6.2341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1703535">Purdue et al. (1990)</a> found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: P11L, gly170-to-arg (G170R; <a href="#0013">604285.0013</a>), and ile340-to-met (I340M; <a href="#0014">604285.0014</a>). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1703535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Purdue, P. E., Allsop, J., Isaya, G., Rosenberg, L. E., Danpure, C. J. <strong>Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.</strong> Proc. Nat. Acad. Sci. 88: 10900-10904, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961759</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961759">Purdue et al. (1991)</a> showed that the P11L variant is necessary and sufficient for the generation of a mitochondrial targeting sequence (MTS) in the AGT protein. The N-terminal 19 amino acids of AGT with this substitution were sufficient to direct mouse cytosolic dihydrofolate reductase to mitochondria. Although the P11L mutation creates an MTS, the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. <a href="#17" class="mim-tip-reference" title="Purdue, P. E., Allsop, J., Isaya, G., Rosenberg, L. E., Danpure, C. J. <strong>Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.</strong> Proc. Nat. Acad. Sci. 88: 10900-10904, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961759</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961759">Purdue et al. (1991)</a> also studied the region of normal human AGT cDNA directly upstream of the coding region. They found that this sequence appears to correspond to an ancestral MTS deleted from the human coding region by a point mutation at the initiation codon. The reestablishment of this initiation codon produced an active MTS that was different from that observed in hyperoxaluria patients. The protein sorting defect found in approximately one-third of patients with primary hyperoxaluria type I is unique. The subcellular distribution of AGT is species-specific. The rat, for example, is one of a number of species in which AGT is a naturally occurring mitochondrial protein. In human AGT cDNA, the region homologous to that encoding the rat AGT MTS lies within the 5-prime untranslated region, being excluded from the open reading frame due to a coding difference (ATG in rat, ATA in human) at the rat-equivalent translation initiation site. The evolutionary loss of this ATG codon appears to explain the exclusive peroxisomal localization of human AGT; reestablishment of this codon could represent another mechanism for mitochondrial mistargeting of AGT in humans. Whereas humans, rabbits, and guinea pigs do not target AGT to the mitochondrion, rats, cats, and marmosets are among those species that do. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1961759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Salido, E. C., Li, X. M., Lu, Y., Wang, X., Santana, A., Roy-Chowdhury, N., Torres, A., Shapiro, L. J., Roy-Chowdhury, J. <strong>Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer.</strong> Proc. Nat. Acad. Sci. 103: 18249-18254, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110443[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/10.1073/pnas.0607218103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110443">Salido et al. (2006)</a> showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110443" 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 P11L and G170R variants occur with other AGXT polymorphisms on the minor allele haplotype, which is population-dependent. The frequency of this minor allele haplotype is 10 to 20% in Caucasians, but only 2% in Japanese. In primary hyperoxaluria type I, the frequency is about 46% (<a href="#27" class="mim-tip-reference" title="Williams, E. L., Acquaviva, C., Amoroso, A., Chevalier, F., Coulter-Mackie, M., Monico, C. G., Giachino, D., Owen, T., Robbiano, A., Salido, E., Waterham, H., Rumsby, G. <strong>Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.</strong> Hum. Mutat. 30: 910-917, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19479957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19479957</a>] [<a href="https://doi.org/10.1002/humu.21021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19479957">Williams et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19479957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using recombinant epitope-tagged proteins expressed in E. coli, <a href="#12" class="mim-tip-reference" title="Lumb, M. J., Danpure, C. J. <strong>Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.</strong> J. Biol. Chem. 275: 36415-36422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10960483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10960483</a>] [<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10960483">Lumb and Danpure (2000)</a> determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. Recombinant AGT expressed from the major allele was functionally similar to human liver AGT in binding alanine, glyoxylate, and pyridoxal phosphate in pH optima and in the ability to dimerize. However, recombinant AGT carrying the P11L and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. Other mutations that segregate almost exclusively with the minor allele, G41R (<a href="#0005">604285.0005</a>), F152I (<a href="#0006">604285.0006</a>), and I244T (<a href="#0007">604285.0007</a>), are associated with absence or near absence of immunoreactive AGT protein and catalytic activity. When AGT(R41) was expressed alone on the background of the major AGT allele, it showed 7% residual activity; however, the other substitutions showed between 44 and 59% residual activity and were predicted to be innocuous in the absence of P11L. The G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10960483" 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> rs121908521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908521;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/rs121908521?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=rs121908521" 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=rs121908521" 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=RCV000005996 OR RCV003555932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005996, RCV003555932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005996...</a>
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<p><a href="#17" class="mim-tip-reference" title="Purdue, P. E., Allsop, J., Isaya, G., Rosenberg, L. E., Danpure, C. J. <strong>Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.</strong> Proc. Nat. Acad. Sci. 88: 10900-10904, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961759</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961759">Purdue et al. (1991)</a> identified a 74-bp duplication within the first intron of the AGXT gene and showed that the duplication is closely linked to 2 point mutations associated with the peroxisome-to-mitochondrion mistargeting. They showed that the duplication is useful in identifying hyperoxaluria (<a href="/entry/259900">259900</a>) patients with so-called mAGT (i.e., mitochondrial AGT) and also facilitates the identification of additional mutations in the non-mAGT allele of compound heterozygotes with mAGT. They illustrated this fact by identification of a tyr66-to-ter (Y66X) mutation resulting from a C-to-G change in exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1961759" 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> rs121908522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908522;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/rs121908522?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=rs121908522" 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=rs121908522" 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=RCV000005997 OR RCV001851685 OR RCV003234894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005997, RCV001851685, RCV003234894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005997...</a>
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<p><a href="#19" class="mim-tip-reference" title="Purdue, P. E., Lumb, M. J., Allsop, J., Minatogawa, Y., Danpure, C. J. <strong>A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1.</strong> Genomics 13: 215-218, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349575</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90225-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349575">Purdue et al. (1992)</a> found a G-to-A transition at nucleotide 367 of the AGXT cDNA, which was predicted to cause a glycine-to-glutamate substitution at residue 82 (G82Q) of the AGT protein. The mutation was located in exon 2 and led to the loss of an AvaI restriction site. The patient was homozygous. The same mutation was found in homozygous state in 1 related and 2 unrelated patients with type I primary hyperoxaluria (<a href="/entry/259900">259900</a>). One other phenotypically similar patient lacked the mutation, however. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1349575" 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="Lumb, M. J., Danpure, C. J. <strong>Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.</strong> J. Biol. Chem. 275: 36415-36422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10960483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10960483</a>] [<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10960483">Lumb and Danpure (2000)</a> noted that AGT carrying the G82E substitution does not affect the stability or mitochondria targeting of AGT, but eliminates its catalytic activity. Using recombinant proteins expressed in E. coli, they showed that AGT with this substitution did not bind the pyridoxal phosphate cofactor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10960483" 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> rs121908523 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908523;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/rs121908523?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=rs121908523" 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=rs121908523" 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=RCV000005998 OR RCV000662315 OR RCV001221086 OR RCV002509145" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005998, RCV000662315, RCV001221086, RCV002509145" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005998...</a>
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<p><a href="#7" class="mim-tip-reference" title="Danpure, C. J., Purdue, P. E., Fryer, P., Griffiths, S., Allsop, J., Lumb, M. J., Guttridge, K. M., Jennings, P. R., Scheinman, J. I., Mauer, S. M., Davidson, N. O. <strong>Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.</strong> Am. J. Hum. Genet. 53: 417-432, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101040</a>]" pmid="8101040">Danpure et al. (1993)</a> observed 2 patients with hyperoxaluria (<a href="/entry/259900">259900</a>) who were compound heterozygotes for 2 previously unrecognized point mutations that caused gly41-to-arg (G41R) and phe152-to-ile (<a href="#0006">604285.0006</a>) amino acid substitutions. Both were homozygous for the pro11-to-leu polymorphism that had previously been found with a high allelic frequency in the normal populations. They suggested that the phe152-to-ile substitution, which is located in a highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the pro11-to-leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. The gly41-to-arg substitution, either in combination with the pro11-to-leu polymorphism or by itself, was predicted to be responsible for the intraperoxisomal aggregation of AGT protein. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. They presented electromicrographic views of the peroxisomal cores. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using recombinant epitope-tagged proteins expressed in E. coli, <a href="#12" class="mim-tip-reference" title="Lumb, M. J., Danpure, C. J. <strong>Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.</strong> J. Biol. Chem. 275: 36415-36422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10960483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10960483</a>] [<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10960483">Lumb and Danpure (2000)</a> determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. They found that when the G41R mutation (AGT(R41)) was expressed alone on the background of the major AGT allele, it showed 7% residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10960483" 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 expressing the major allele of AGT carrying the G41R substitution in E. coli, <a href="#3" class="mim-tip-reference" title="Cellini, B., Montioli, R., Paiardini, A., Lorenzetto, A., Voltattorni, C. B. <strong>Molecular insight into the synergism between the minor allele of human liver peroxisomal alanine:glyoxylate aminotransferase and the F152I mutation.</strong> J. Biol. Chem. 284: 8349-8358, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19155213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19155213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19155213[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.M808965200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19155213">Cellini et al. (2009)</a> showed that the G41R substitution resulted in significantly reduced AGT activity that was independent of the P11L substitution. The G41R substitution alone resulted in about 7% residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19155213" 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="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al. (2013)</a> found that the G41R mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. They also found that whereas the other missense mutations they tested were able to form dimers and were catalytically active, the G41R mutant aggregates and is inactive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" 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> rs121908524 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908524;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/rs121908524?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=rs121908524" 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=rs121908524" 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=RCV000005999 OR RCV000727639 OR RCV000779687" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005999, RCV000727639, RCV000779687" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005999...</a>
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<p>See <a href="#0005">604285.0005</a> and <a href="#7" class="mim-tip-reference" title="Danpure, C. J., Purdue, P. E., Fryer, P., Griffiths, S., Allsop, J., Lumb, M. J., Guttridge, K. M., Jennings, P. R., Scheinman, J. I., Mauer, S. M., Davidson, N. O. <strong>Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.</strong> Am. J. Hum. Genet. 53: 417-432, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101040</a>]" pmid="8101040">Danpure et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101040" 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>AGT exists as 2 polymorphic variants, a major allele (AGT-Ma) and a minor allele (AGT-Mi) (see <a href="#0002">604285.0002</a>), which shows lower AGT activity compared with AGT-Ma. AGT-Mi also causes PH1 only when combined with specific mutations, including F152I. <a href="#3" class="mim-tip-reference" title="Cellini, B., Montioli, R., Paiardini, A., Lorenzetto, A., Voltattorni, C. B. <strong>Molecular insight into the synergism between the minor allele of human liver peroxisomal alanine:glyoxylate aminotransferase and the F152I mutation.</strong> J. Biol. Chem. 284: 8349-8358, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19155213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19155213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19155213[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.M808965200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19155213">Cellini et al. (2009)</a> showed that the F152I substitution does not affect the transaminase activity of AGT-Mi, but plays a role in stabilizing the aminated cofactor, pyridoxamine 5-prime-phosphate (PMP) produced during the L-alanine half-transamination reaction. The F152I substitution in both AGT-Mi and AGT-Ma caused the premature release of PMP, resulting in the formation of the apoenzyme in both isoforms. In the context of AGT-Mi, however, F152I additionally causes destabilization of the enzyme at physiologic temperatures, with concomitant protein aggregation and loss of enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19155213" 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="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al. (2013)</a> found that the F152I mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" 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> rs121908525 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908525;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/rs121908525?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=rs121908525" 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=rs121908525" 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=RCV000006000 OR RCV000586265 OR RCV000662316 OR RCV001042614 OR RCV003407286" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006000, RCV000586265, RCV000662316, RCV001042614, RCV003407286" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006000...</a>
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<p>One of the mutations clustered in exon 7 of the AGXT gene identified by <a href="#25" class="mim-tip-reference" title="von Schnakenburg, C., Rumsby, G. <strong>Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.</strong> J. Med. Genet. 34: 489-492, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192270</a>] [<a href="https://doi.org/10.1136/jmg.34.6.489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192270">von Schnakenburg and Rumsby (1997)</a> in studies of 79 patients with type I primary hyperoxaluria (PH1; <a href="/entry/259900">259900</a>) was an 853T-C transition that led to a predicted ile244-to-thr (I244T) substitution. This was found in homozygous or heterozygous state in 9% of patients, making it the second most common mutation found up to that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Santana, A., Salido, E., Torres, A., Shapiro, L. J. <strong>Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.</strong> Proc. Nat. Acad. Sci. 100: 7277-7282, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12777626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12777626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12777626[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/10.1073/pnas.1131968100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12777626">Santana et al. (2003)</a> reported that most of the AGXT alleles detected in patients from the Canary Islands with PH1 carry the I244T mutation; 14 of 16 patients they studied were homozygous for this mutation and shared in their haplotypes 4 polymorphisms within AGXT and regional microsatellites (AGXT*LTM), consistent with a founder effect. <a href="#23" class="mim-tip-reference" title="Santana, A., Salido, E., Torres, A., Shapiro, L. J. <strong>Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.</strong> Proc. Nat. Acad. Sci. 100: 7277-7282, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12777626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12777626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12777626[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/10.1073/pnas.1131968100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12777626">Santana et al. (2003)</a> investigated the consequence of these amino acid changes and found that although I244T alone did not affect AGXT activity or subcellular localization (i.e., mitochondria vs peroxisomes), when present in the same protein molecule as L11P (see <a href="#0002">604285.0002</a>), it resulted in loss of enzymatic activity in soluble cell extracts. Like its normal counterpart, the AGXT*LTM protein was present in the peroxisomes but was insoluble in detergent-free buffers. The L11P polymorphism behaved as an intragenic modifier of the I244T mutation, with the resulting protein undergoing stable interaction with molecular chaperones and temperature-sensitive aggregation. Among various chemical chaperones tested in cell culture, betaine substantially improved the solubility of the mutant protein and the enzymatic activity in cell lysates. <a href="#23" class="mim-tip-reference" title="Santana, A., Salido, E., Torres, A., Shapiro, L. J. <strong>Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.</strong> Proc. Nat. Acad. Sci. 100: 7277-7282, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12777626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12777626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12777626[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/10.1073/pnas.1131968100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12777626">Santana et al. (2003)</a> concluded that the synergistic effect of P11L with I244T causes PH1, a protein conformational disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12777626" 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="Fargue, S., Lewin, J., Rumsby, G., Danpure, C. J. <strong>Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.</strong> J. Biol. Chem. 288: 2475-2484, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23229545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23229545</a>] [<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23229545">Fargue et al. (2013)</a> found that the I244T mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23229545" 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> rs121908526 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908526;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/rs121908526?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=rs121908526" 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=rs121908526" 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=RCV000006001 OR RCV001070457" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006001, RCV001070457" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006001...</a>
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<p>In a patient with type I primary hyperoxaluria (<a href="/entry/259900">259900</a>), <a href="#25" class="mim-tip-reference" title="von Schnakenburg, C., Rumsby, G. <strong>Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.</strong> J. Med. Genet. 34: 489-492, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192270</a>] [<a href="https://doi.org/10.1136/jmg.34.6.489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192270">von Schnakenburg and Rumsby (1997)</a> found a homozygous 819C-T transition in the AGXT gene that mutated codon 233 from arginine to cysteine (R233C). A mutation in the adjacent nucleotide, 820G-A, mutated the same codon from arginine to histidine (<a href="#0009">604285.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 HYPEROXALURIA, PRIMARY, TYPE I</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908527 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908527;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/rs121908527?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=rs121908527" 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=rs121908527" 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=RCV000006002 OR RCV001385647" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006002, RCV001385647" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006002...</a>
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<p>See <a href="#0008">604285.0008</a> and <a href="#25" class="mim-tip-reference" title="von Schnakenburg, C., Rumsby, G. <strong>Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.</strong> J. Med. Genet. 34: 489-492, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192270</a>] [<a href="https://doi.org/10.1136/jmg.34.6.489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192270">von Schnakenburg and Rumsby (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192270" 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">rs121908528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908528;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=rs121908528" 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=rs121908528" 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=RCV000006003 OR RCV003555933" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006003, RCV003555933" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006003...</a>
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<p>In a patient with type I primary hyperoxaluria (<a href="/entry/259900">259900</a>), <a href="#25" class="mim-tip-reference" title="von Schnakenburg, C., Rumsby, G. <strong>Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.</strong> J. Med. Genet. 34: 489-492, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192270</a>] [<a href="https://doi.org/10.1136/jmg.34.6.489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192270">von Schnakenburg and Rumsby (1997)</a> found heterozygosity for an 860G-A transition in exon 7 of the AGXT gene, introducing a stop codon at amino acid residue 246. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MOVED TO <a href="/entry/604285#0002">604285.0002</a></strong>
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<strong>.0012 HYPEROXALURIA, PRIMARY, TYPE I</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908530;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/rs121908530?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=rs121908530" 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=rs121908530" 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=RCV000006004 OR RCV001851686 OR RCV002265548 OR RCV004798718" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006004, RCV001851686, RCV002265548, RCV004798718" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006004...</a>
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<p>In a study of 15 unrelated Italian patients with type I primary hyperoxaluria (<a href="/entry/259900">259900</a>), <a href="#16" class="mim-tip-reference" title="Pirulli, D., Puzzer, D., Ferri, L., Crovella, S., Amoroso, A., Ferrettini, C., Marangella, M., Mazzola, G., Florian, F. <strong>Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine:glyoxylate aminotransferase gene.</strong> Hum. Genet. 104: 523-525, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453743</a>] [<a href="https://doi.org/10.1007/s004390050998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453743">Pirulli et al. (1999)</a> found that the second most frequent AGXT allele carried a gly158-to-arg (G158R) mutation, with a prevalence of 13%. The mutation resulted from a 588G-A transition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453743" 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="0013" class="mim-anchor"></a>
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<strong>.0013 HYPEROXALURIA, PRIMARY, TYPE I</strong>
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AGXT, GLY170ARG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032681 OR RCV000432954 OR RCV000589490 OR RCV003407388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032681, RCV000432954, RCV000589490, RCV003407388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032681...</a>
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<p><a href="#4" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rumsby, G. <strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong> Molec. Genet. Metab. 83: 38-46, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15464418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15464418</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15464418">Coulter-Mackie and Rumsby (2004)</a> noted that the gly170-to-arg (G170R) mutation results from a 508G-A (with position 1 being the first coding nucleotide) transition in exon 4 of AGXT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15464418" 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="#21" class="mim-tip-reference" title="Purdue, P. E., Takada, Y., Danpure, C. J. <strong>Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.</strong> J. Cell Biol. 111: 2341-2351, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1703535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1703535</a>] [<a href="https://doi.org/10.1083/jcb.111.6.2341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1703535">Purdue et al. (1990)</a> found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: pro11-to-leu (P11L; <a href="#0002">604285.0002</a>), G170R, and ile340-to-met (I340M; <a href="#0014">604285.0014</a>). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1703535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Purdue, P. E., Allsop, J., Isaya, G., Rosenberg, L. E., Danpure, C. J. <strong>Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.</strong> Proc. Nat. Acad. Sci. 88: 10900-10904, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961759</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961759">Purdue et al. (1991)</a> showed that although the P11L mutation creates a mitochondrial targeting sequence (MTS), the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1961759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Salido, E. C., Li, X. M., Lu, Y., Wang, X., Santana, A., Roy-Chowdhury, N., Torres, A., Shapiro, L. J., Roy-Chowdhury, J. <strong>Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer.</strong> Proc. Nat. Acad. Sci. 103: 18249-18254, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110443[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/10.1073/pnas.0607218103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110443">Salido et al. (2006)</a> showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 15 unrelated Italian patients with type I primary hyperoxaluria, <a href="#16" class="mim-tip-reference" title="Pirulli, D., Puzzer, D., Ferri, L., Crovella, S., Amoroso, A., Ferrettini, C., Marangella, M., Mazzola, G., Florian, F. <strong>Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine:glyoxylate aminotransferase gene.</strong> Hum. Genet. 104: 523-525, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453743</a>] [<a href="https://doi.org/10.1007/s004390050998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453743">Pirulli et al. (1999)</a> found that the most frequent AGXT allele carried the G170R mutation, with a prevalence of 30%. The mutation results from a 630G-A transition. The mutation was found on the background of the minor allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453743" 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="Lumb, M. J., Danpure, C. J. <strong>Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.</strong> J. Biol. Chem. 275: 36415-36422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10960483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10960483</a>] [<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10960483">Lumb and Danpure (2000)</a> found that the G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10960483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 RECLASSIFIED - ALANINE-GLYOXYLATE AMINOTRANSFERASE POLYMORPHISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs4426527 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4426527;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/rs4426527?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=rs4426527" 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=rs4426527" 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=RCV000032682 OR RCV000247828 OR RCV001519689" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032682, RCV000247828, RCV001519689" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032682...</a>
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<p>This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.</p><p><a href="#4" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rumsby, G. <strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong> Molec. Genet. Metab. 83: 38-46, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15464418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15464418</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15464418">Coulter-Mackie and Rumsby (2004)</a> noted that the ile340-to-met (I340M) substitution results from a 1020A-G transition exon 10 of AGXT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15464418" 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="Lumb, M. J., Danpure, C. J. <strong>Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.</strong> J. Biol. Chem. 275: 36415-36422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10960483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10960483</a>] [<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10960483">Lumb and Danpure (2000)</a> found that recombinant AGT carrying the P11L (<a href="#0002">604285.0002</a>) and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10960483" 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">rs180177201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177201;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=rs180177201" 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=rs180177201" 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=RCV000128800 OR RCV000779688 OR RCV000800941 OR RCV001849312 OR RCV003415938 OR RCV003993816" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128800, RCV000779688, RCV000800941, RCV001849312, RCV003415938, RCV003993816" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128800...</a>
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<p><a href="#4" class="mim-tip-reference" title="Coulter-Mackie, M. B., Rumsby, G. <strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong> Molec. Genet. Metab. 83: 38-46, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15464418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15464418</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15464418">Coulter-Mackie and Rumsby (2004)</a> stated that the 33_34insC mutation in exon 1 of the AGXT gene, which occurs on the background of the major allele, is found at a frequency of 12% in affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15464418" 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="#Bourke1972" class="mim-tip-reference" title="Bourke, E., Frindt, G., Flynn, P., Schreiner, G. E. <strong>Primary hyperoxaluria with normal alpha-ketoglutarate:glyoxylate carboligase activity: treatment with isocarboxazid.</strong> Ann. Intern. Med. 76: 279-284, 1972.">Bourke et al. (1972)</a>; <a href="#Danpure1987" class="mim-tip-reference" title="Danpure, C. J., Jennings, P. R., Watts, R. W. E. <strong>Enzymological diagnosis of primary hyperoxaluria type 1 by measurement of hepatic alanine:glyoxylate aminotransferase activity.</strong> Lancet 329: 289-291, 1987. Note: Originally Volume I.">Danpure et al. (1987)</a>; <a href="#Danpure1988" class="mim-tip-reference" title="Danpure, C. J. <strong>Personal Communication.</strong> Middlesex, England 6/16/1988.">Danpure (1988)</a>; <a href="#Danpure1993" class="mim-tip-reference" title="Danpure, C. J. <strong>Primary hyperoxaluria type 1 and peroxisome-to-mitochondrion mistargeting of alanine:glyoxylate aminotransferase.</strong> Biochimie 75: 309-315, 1993.">Danpure
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(1993)</a>; <a href="#Purdue1991" class="mim-tip-reference" title="Purdue, P. E., Lumb, M. J., Fox, M., Griffo, G., Hamon-Benais, C., Povey, S., Danpure, C. J. <strong>Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.</strong> Genomics 10: 34-42, 1991.">Purdue et al. (1991)</a>; <a href="#Purdue1991" class="mim-tip-reference" title="Purdue, P. E., Lumb, M. J., Fox, M., Griffo, G., Hamon-Benais, C., Povey, S., Danpure, C. J. <strong>Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.</strong> Genomics 10: 34-42, 1991.">Purdue et al. (1991)</a>; <a href="#Watts1987" class="mim-tip-reference" title="Watts, R. W. E., Calne, R. Y., Rolles, K., Danpure, C. J., Morgan, S. H., Mansell, M. A., Williams, R., Purkiss, P. <strong>Successful treatment of primary hyperoxaluria type I by combined hepatic and renal transplantation.</strong> Lancet 330: 474-475, 1987. Note: Originally Volume II.">Watts et al.
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Ann. Intern. Med. 76: 279-284, 1972.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5009594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5009594</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5009594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-004-1191-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M808965200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2004.08.009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(87)92023-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0014-5793(86)80563-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0300-9084(93)90091-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/bies.950190409" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M112.432617" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M006693200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90225-h" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Purdue1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Purdue, P. E., Lumb, M. J., Fox, M., Griffo, G., Hamon-Benais, C., Povey, S., Danpure, C. J.
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<strong>Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.</strong>
|
|
Genomics 10: 34-42, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2045108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2045108</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2045108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90481-s" target="_blank">Full Text</a>]
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</p>
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<a id="21" class="mim-anchor"></a>
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<a id="Purdue1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Purdue, P. E., Takada, Y., Danpure, C. J.
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|
<strong>Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.</strong>
|
|
J. Cell Biol. 111: 2341-2351, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1703535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1703535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1703535" 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/10.1083/jcb.111.6.2341" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Salido2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Salido, E. C., Li, X. M., Lu, Y., Wang, X., Santana, A., Roy-Chowdhury, N., Torres, A., Shapiro, L. J., Roy-Chowdhury, J.
|
|
<strong>Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18249-18254, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110443[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=17110443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0607218103" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Santana2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Santana, A., Salido, E., Torres, A., Shapiro, L. J.
|
|
<strong>Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 7277-7282, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12777626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12777626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12777626[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=12777626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1131968100" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Takada1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Takada, Y., Kaneko, N., Esumi, H., Purdue, P. E., Danpure, C. J.
|
|
<strong>Human peroxisomal L-alanine:glyoxylate aminotransferase: evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.</strong>
|
|
Biochem. J. 268: 517-520, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2363689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2363689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2363689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1042/bj2680517" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="von Schnakenburg1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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von Schnakenburg, C., Rumsby, G.
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<strong>Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.</strong>
|
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J. Med. Genet. 34: 489-492, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192270" 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/10.1136/jmg.34.6.489" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Watts1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watts, R. W. E., Calne, R. Y., Rolles, K., Danpure, C. J., Morgan, S. H., Mansell, M. A., Williams, R., Purkiss, P.
|
|
<strong>Successful treatment of primary hyperoxaluria type I by combined hepatic and renal transplantation.</strong>
|
|
Lancet 330: 474-475, 1987. Note: Originally Volume II.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2887776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2887776</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2887776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(87)91791-0" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Williams2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williams, E. L., Acquaviva, C., Amoroso, A., Chevalier, F., Coulter-Mackie, M., Monico, C. G., Giachino, D., Owen, T., Robbiano, A., Salido, E., Waterham, H., Rumsby, G.
|
|
<strong>Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.</strong>
|
|
Hum. Mutat. 30: 910-917, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19479957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19479957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19479957" 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/10.1002/humu.21021" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 2/5/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 8/2/2010<br>Cassandra L. Kniffin - updated : 9/4/2009<br>Patricia A. Hartz - updated : 2/2/2007<br>Victor A. McKusick - updated : 4/27/2005<br>Victor A. McKusick - updated : 7/14/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/5/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 11/07/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/21/2018<br>carol : 08/20/2018<br>carol : 11/01/2016<br>joanna : 05/28/2014<br>alopez : 2/5/2013<br>alopez : 2/5/2013<br>alopez : 2/5/2013<br>alopez : 2/4/2013<br>terry : 8/2/2010<br>carol : 7/14/2010<br>wwang : 9/22/2009<br>ckniffin : 9/4/2009<br>terry : 4/3/2009<br>wwang : 12/12/2008<br>carol : 12/2/2008<br>alopez : 2/2/2007<br>terry : 12/13/2005<br>tkritzer : 5/10/2005<br>terry : 4/27/2005<br>carol : 8/13/2003<br>tkritzer : 7/23/2003<br>terry : 7/14/2003<br>mgross : 11/5/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604285
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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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ALANINE-GLYOXYLATE AMINOTRANSFERASE; AGXT
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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">
|
|
AGXT1<br />
|
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AGT<br />
|
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SERINE-PYRUVATE AMINOTRANSFERASE; SPT; SPAT
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: AGXT</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> 65520001;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 2q37.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:240,868,824-240,880,500 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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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">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
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<tr>
|
|
<td rowspan="1">
|
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<span class="mim-font">
|
|
2q37.3
|
|
</span>
|
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</td>
|
|
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<td>
|
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<span class="mim-font">
|
|
Hyperoxaluria, primary, type 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
259900
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>The AGXT gene encodes alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44), whose activity is largely confined to peroxisomes in the liver. AGT also shows serine:pyruvate aminotransferase activity (EC 2.6.1.51) (Noguchi et al., 1978). </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>Takada et al. (1990) isolated clones corresponding to the AGT gene from a human liver cDNA library. The deduced 392-residue protein had a calculated molecular mass of 43 kD. The human peroxisomal AGT showed about 78% amino acid sequence identity with rat mitochondrial AGT. The putative pyridoxal phosphate-binding lysine residue at position 209 is conserved. A comparison of the 5-prime sequences indicated that the N-terminal 22 amino acids of the rat translation product are absent from the human protein. The loss of this mitochondrial targeting sequence (MTS) signal during evolution may partly explain the species differences in intracellular localization of AGT. </p><p>Purdue et al. (1990) isolated a clone encoding human liver-specific peroxisomal AGT, also called AGXT. The nucleotide sequences corresponded to the sequence of the AGT cDNA characterized by Takada et al. (1990). The results of genomic Southern blotting indicated that the human AGT gene is a probably single copy. </p><p>Cellini et al. (2009) noted that AGT functions as a dimer, and each AGT monomer consists of an N-terminal arm involved in dimer formation, a large catalytic domain containing an active site lys209, and a smaller C-terminal domain. One pyridoxal 5-prime-phosphate (PLP) cofactor binds per subunit and is present in a Schiff base linkage with lys209. </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>Purdue et al. (1990) determined that the coding sequence of the AGXT gene spans 10 kb and 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">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By in situ hybridization and PCR analysis of rodent/human somatic cell hybrids, Purdue et al. (1991) mapped the AGXT gene to chromosome 2q36-q37. </p><p>Mori et al. (1992) showed by in situ hybridization that a single gene for this enzyme in the rat, symbolized SPT/AGT, is located on chromosome 9q34-q36. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Primary hyperoxaluria type 1 (259900) is an autosomal recessive disorder caused by deficiency of alanine:glyoxylate aminotransferase (AGT), characterized by progressive kidney failure due to renal deposition of calcium oxalate. In about one-third of patients residual enzyme activity is up to 60% of mean normal, but in most of these patients AGT is mistargeted to mitochondria instead of peroxisomes. The mistargeting mutation gly170-to-arg (G170R; 604285.0013) is the most common mutation among Caucasian patients, with a frequency of 23 to 27%. The G170R mutation always occurs on the background of the minor allele (see 604285.0002), with which it interacts synergistically (summary by Coulter-Mackie and Rumsby, 2004). </p><p>Danpure and Jennings (1986) demonstrated that total AGXT levels were reduced in 2 patients with type I primary hyperoxaluria (259900). </p><p>In a patient with primary hyperoxaluria type I (HP1; 259900), Nishiyama et al. (1991) identified a mutation in the AGXT gene (S205P; 604285.0001). SPT activity was approximately 1% of that in control liver. </p><p>The intermediary metabolic enzyme AGT contains a pro11-to-leu (P11L; 604285.0002) polymorphism that decreases its catalytic activity by a factor of 3 and causes a small proportion to be mistargeted from its normal intracellular location in the peroxisomes to the mitochondria. These changes were predicted to have significant effects on the synthesis and excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract (summary by Danpure, 1997). </p><p>In 15 unrelated Italian patients with type I primary hyperoxaluria, Pirulli et al. (1999) 8 novel mutations in the AGXT gene (see, e.g., G158R, 604285.0012). The most frequent mutation was G170R (604285.0013), accounting for 30% of alleles, followed by G158R, with a 13% frequency. Ten of the 15 patients were homozygotes; in only 1 case were the parents identified as first cousins. </p><p>In a mutation update of the AGXT gene, Williams et al. (2009) stated that 146 mutations had been identified, with all exons of the AGXT gene represented. The authors identified 50 novel mutations in patients with HP1. There were no apparent genotype/phenotype correlations. </p><p>Fargue et al. (2013) showed that 3 disease-causing missense mutations, I244T (604285.0007), F152I (604285.0006), and G41R (604285.0005), which occur on the background of the minor allele characterized by the P11L polymorphism, can, like G170R, unmask the cryptic P11L-generated mitochondrial targeting sequence and result in AGT protein being mistargeted to mitochondria. These 4 missense mutations together constitute 40% of HP1 alleles. </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>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Based on the evolution of AGT targeting in mammals, Danpure (1997) hypothesized that the common P11L polymorphism would be advantageous for individuals who have a meat-rich diet, but disadvantageous for those who do not. If true, the frequency of distribution of P11L in different extant human populations should have been shaped by their dietary history so that it should be more common in populations with predominantly meat-eating ancestral diets than it is in populations in which the ancestral diet was predominantly vegetarian. In a study of frequency of P11L in 11 different human populations with divergent ancestral dietary lifestyles, Caldwell et al. (2004) found evidence in support of the hypothesis: the highest allelic frequency, 27.9%, was found in the Saami, a population with a very meat-rich ancestral diet; the lowest, 2.3%, was found in Chinese, who were likely to have had a more mixed ancestral diet. The differences in P11L frequency between some populations (particularly Saami vs Chinese) was very high when compared with neutral loci, suggesting that its frequency might have been shaped by dietary selection pressure. </p><p>Fargue et al. (2013) stated that the minor allele characterized by the P11L polymorphism occurs in 15 to 20% of European and North American populations. </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Salido et al. (2006) found that Agt1-null mice grew and developed normally; however they developed hyperoxaluria and crystalluria. About half of the male mice in mixed genetic background developed calcium oxalate urinary stones. Severe nephrocalcinosis and renal failure developed after pharmacologic enhancement of oxalate production. Hepatic expression of human AGT1 by adenoviral vector-mediated gene transfer in Agt1 -/- mice normalized urinary oxalate excretion and prevented oxalate crystalluria. Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expression of transgenic AGT1 was predominantly localized to hepatocellular peroxisomes. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 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 HYPEROXALURIA, PRIMARY, TYPE I</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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AGXT, SER205PRO
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<br />
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SNP: rs121908520,
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gnomAD: rs121908520,
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ClinVar: RCV000005994, RCV000420710
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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>Nishiyama et al. (1991) obtained cDNA clones for serine:pyruvate aminotransferase from a cDNA library constructed from the liver of a patient with primary hyperoxaluria type I (HP1; 259900) in which the SPT activity was approximately 1% of that in control liver. Genetic analysis identified a 634T-C transition in the AGXT gene, resulting in a ser205-to-pro (S205P) substitution. The T-to-C conversion created a new SmaI site. </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>.0002 RECLASSIFIED - ALANINE-GLYOXYLATE AMINOTRANSFERASE POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AGXT, PRO11LEU ({dbSNP rs34116584})
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<br />
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SNP: rs121908529, rs34116584,
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gnomAD: rs121908529, rs34116584,
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ClinVar: RCV000005995, RCV000032681, RCV000173049, RCV000432954, RCV000589490, RCV001513552, RCV003407388, RCV003468718
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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>This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.</p><p>The pro11-to-leu substitution (P11L) is the primary polymorphism that defines the minor allele of AGXT that occurs with an allele frequency of 15 to 20% in European and North American populations and 50% of patients with primary hyperoxaluria type I (HP1; 259900). The absence of these polymorphisms defines the major allele. The P11L replacement creates a hidden N-terminal mitochondrial targeting sequence that can be unmasked by additional amino acid substitutions in cis, resulting in disease (summary by Fargue et al., 2013). </p><p>Coulter-Mackie and Rumsby (2004) noted that the P11L substitution results from a 32C-T transition in exon 1 of AGXT. </p><p>Purdue et al. (1990) found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: P11L, gly170-to-arg (G170R; 604285.0013), and ile340-to-met (I340M; 604285.0014). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import. </p><p>Purdue et al. (1991) showed that the P11L variant is necessary and sufficient for the generation of a mitochondrial targeting sequence (MTS) in the AGT protein. The N-terminal 19 amino acids of AGT with this substitution were sufficient to direct mouse cytosolic dihydrofolate reductase to mitochondria. Although the P11L mutation creates an MTS, the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. Purdue et al. (1991) also studied the region of normal human AGT cDNA directly upstream of the coding region. They found that this sequence appears to correspond to an ancestral MTS deleted from the human coding region by a point mutation at the initiation codon. The reestablishment of this initiation codon produced an active MTS that was different from that observed in hyperoxaluria patients. The protein sorting defect found in approximately one-third of patients with primary hyperoxaluria type I is unique. The subcellular distribution of AGT is species-specific. The rat, for example, is one of a number of species in which AGT is a naturally occurring mitochondrial protein. In human AGT cDNA, the region homologous to that encoding the rat AGT MTS lies within the 5-prime untranslated region, being excluded from the open reading frame due to a coding difference (ATG in rat, ATA in human) at the rat-equivalent translation initiation site. The evolutionary loss of this ATG codon appears to explain the exclusive peroxisomal localization of human AGT; reestablishment of this codon could represent another mechanism for mitochondrial mistargeting of AGT in humans. Whereas humans, rabbits, and guinea pigs do not target AGT to the mitochondrion, rats, cats, and marmosets are among those species that do. </p><p>Salido et al. (2006) showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria. </p><p>The P11L and G170R variants occur with other AGXT polymorphisms on the minor allele haplotype, which is population-dependent. The frequency of this minor allele haplotype is 10 to 20% in Caucasians, but only 2% in Japanese. In primary hyperoxaluria type I, the frequency is about 46% (Williams et al., 2009). </p><p>Using recombinant epitope-tagged proteins expressed in E. coli, Lumb and Danpure (2000) determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. Recombinant AGT expressed from the major allele was functionally similar to human liver AGT in binding alanine, glyoxylate, and pyridoxal phosphate in pH optima and in the ability to dimerize. However, recombinant AGT carrying the P11L and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. Other mutations that segregate almost exclusively with the minor allele, G41R (604285.0005), F152I (604285.0006), and I244T (604285.0007), are associated with absence or near absence of immunoreactive AGT protein and catalytic activity. When AGT(R41) was expressed alone on the background of the major AGT allele, it showed 7% residual activity; however, the other substitutions showed between 44 and 59% residual activity and were predicted to be innocuous in the absence of P11L. The G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. </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>.0003 HYPEROXALURIA, PRIMARY, TYPE I</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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|
AGXT, TYR66TER
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<br />
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|
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SNP: rs121908521,
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|
|
gnomAD: rs121908521,
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|
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ClinVar: RCV000005996, RCV003555932
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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>Purdue et al. (1991) identified a 74-bp duplication within the first intron of the AGXT gene and showed that the duplication is closely linked to 2 point mutations associated with the peroxisome-to-mitochondrion mistargeting. They showed that the duplication is useful in identifying hyperoxaluria (259900) patients with so-called mAGT (i.e., mitochondrial AGT) and also facilitates the identification of additional mutations in the non-mAGT allele of compound heterozygotes with mAGT. They illustrated this fact by identification of a tyr66-to-ter (Y66X) mutation resulting from a C-to-G change in exon 2. </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>.0004 HYPEROXALURIA, PRIMARY, TYPE I</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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|
|
|
AGXT, GLY82GLU
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<br />
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SNP: rs121908522,
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gnomAD: rs121908522,
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ClinVar: RCV000005997, RCV001851685, RCV003234894
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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>Purdue et al. (1992) found a G-to-A transition at nucleotide 367 of the AGXT cDNA, which was predicted to cause a glycine-to-glutamate substitution at residue 82 (G82Q) of the AGT protein. The mutation was located in exon 2 and led to the loss of an AvaI restriction site. The patient was homozygous. The same mutation was found in homozygous state in 1 related and 2 unrelated patients with type I primary hyperoxaluria (259900). One other phenotypically similar patient lacked the mutation, however. </p><p>Lumb and Danpure (2000) noted that AGT carrying the G82E substitution does not affect the stability or mitochondria targeting of AGT, but eliminates its catalytic activity. Using recombinant proteins expressed in E. coli, they showed that AGT with this substitution did not bind the pyridoxal phosphate cofactor. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 HYPEROXALURIA, PRIMARY, TYPE I</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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AGXT, GLY41ARG
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<br />
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SNP: rs121908523,
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gnomAD: rs121908523,
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ClinVar: RCV000005998, RCV000662315, RCV001221086, RCV002509145
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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>Danpure et al. (1993) observed 2 patients with hyperoxaluria (259900) who were compound heterozygotes for 2 previously unrecognized point mutations that caused gly41-to-arg (G41R) and phe152-to-ile (604285.0006) amino acid substitutions. Both were homozygous for the pro11-to-leu polymorphism that had previously been found with a high allelic frequency in the normal populations. They suggested that the phe152-to-ile substitution, which is located in a highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the pro11-to-leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. The gly41-to-arg substitution, either in combination with the pro11-to-leu polymorphism or by itself, was predicted to be responsible for the intraperoxisomal aggregation of AGT protein. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. They presented electromicrographic views of the peroxisomal cores. </p><p>Using recombinant epitope-tagged proteins expressed in E. coli, Lumb and Danpure (2000) determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. They found that when the G41R mutation (AGT(R41)) was expressed alone on the background of the major AGT allele, it showed 7% residual activity. </p><p>By expressing the major allele of AGT carrying the G41R substitution in E. coli, Cellini et al. (2009) showed that the G41R substitution resulted in significantly reduced AGT activity that was independent of the P11L substitution. The G41R substitution alone resulted in about 7% residual activity. </p><p>Fargue et al. (2013) found that the G41R mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. They also found that whereas the other missense mutations they tested were able to form dimers and were catalytically active, the G41R mutant aggregates and is inactive. </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>.0006 HYPEROXALURIA, PRIMARY, TYPE I</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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AGXT, PHE152ILE
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<br />
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SNP: rs121908524,
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gnomAD: rs121908524,
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ClinVar: RCV000005999, RCV000727639, RCV000779687
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>See 604285.0005 and Danpure et al. (1993). </p><p>AGT exists as 2 polymorphic variants, a major allele (AGT-Ma) and a minor allele (AGT-Mi) (see 604285.0002), which shows lower AGT activity compared with AGT-Ma. AGT-Mi also causes PH1 only when combined with specific mutations, including F152I. Cellini et al. (2009) showed that the F152I substitution does not affect the transaminase activity of AGT-Mi, but plays a role in stabilizing the aminated cofactor, pyridoxamine 5-prime-phosphate (PMP) produced during the L-alanine half-transamination reaction. The F152I substitution in both AGT-Mi and AGT-Ma caused the premature release of PMP, resulting in the formation of the apoenzyme in both isoforms. In the context of AGT-Mi, however, F152I additionally causes destabilization of the enzyme at physiologic temperatures, with concomitant protein aggregation and loss of enzyme activity. </p><p>Fargue et al. (2013) found that the F152I mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. </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>.0007 HYPEROXALURIA, PRIMARY, TYPE I</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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|
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AGXT, ILE244THR
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<br />
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SNP: rs121908525,
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gnomAD: rs121908525,
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ClinVar: RCV000006000, RCV000586265, RCV000662316, RCV001042614, RCV003407286
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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>One of the mutations clustered in exon 7 of the AGXT gene identified by von Schnakenburg and Rumsby (1997) in studies of 79 patients with type I primary hyperoxaluria (PH1; 259900) was an 853T-C transition that led to a predicted ile244-to-thr (I244T) substitution. This was found in homozygous or heterozygous state in 9% of patients, making it the second most common mutation found up to that time. </p><p>Santana et al. (2003) reported that most of the AGXT alleles detected in patients from the Canary Islands with PH1 carry the I244T mutation; 14 of 16 patients they studied were homozygous for this mutation and shared in their haplotypes 4 polymorphisms within AGXT and regional microsatellites (AGXT*LTM), consistent with a founder effect. Santana et al. (2003) investigated the consequence of these amino acid changes and found that although I244T alone did not affect AGXT activity or subcellular localization (i.e., mitochondria vs peroxisomes), when present in the same protein molecule as L11P (see 604285.0002), it resulted in loss of enzymatic activity in soluble cell extracts. Like its normal counterpart, the AGXT*LTM protein was present in the peroxisomes but was insoluble in detergent-free buffers. The L11P polymorphism behaved as an intragenic modifier of the I244T mutation, with the resulting protein undergoing stable interaction with molecular chaperones and temperature-sensitive aggregation. Among various chemical chaperones tested in cell culture, betaine substantially improved the solubility of the mutant protein and the enzymatic activity in cell lysates. Santana et al. (2003) concluded that the synergistic effect of P11L with I244T causes PH1, a protein conformational disease. </p><p>Fargue et al. (2013) found that the I244T mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. </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>.0008 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
AGXT, ARG233CYS
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<br />
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SNP: rs121908526,
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|
|
gnomAD: rs121908526,
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|
|
ClinVar: RCV000006001, RCV001070457
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|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with type I primary hyperoxaluria (259900), von Schnakenburg and Rumsby (1997) found a homozygous 819C-T transition in the AGXT gene that mutated codon 233 from arginine to cysteine (R233C). A mutation in the adjacent nucleotide, 820G-A, mutated the same codon from arginine to histidine (604285.0009). </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, ARG233HIS
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|
|
|
<br />
|
|
|
|
SNP: rs121908527,
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|
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|
|
|
gnomAD: rs121908527,
|
|
|
|
|
|
ClinVar: RCV000006002, RCV001385647
|
|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>See 604285.0008 and von Schnakenburg and Rumsby (1997). </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
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|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, TRP246TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs121908528,
|
|
|
|
|
|
|
|
ClinVar: RCV000006003, RCV003555933
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with type I primary hyperoxaluria (259900), von Schnakenburg and Rumsby (1997) found heterozygosity for an 860G-A transition in exon 7 of the AGXT gene, introducing a stop codon at amino acid residue 246. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0011 MOVED TO 604285.0002</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, GLY158ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908530,
|
|
|
|
|
|
gnomAD: rs121908530,
|
|
|
|
|
|
ClinVar: RCV000006004, RCV001851686, RCV002265548, RCV004798718
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 15 unrelated Italian patients with type I primary hyperoxaluria (259900), Pirulli et al. (1999) found that the second most frequent AGXT allele carried a gly158-to-arg (G158R) mutation, with a prevalence of 13%. The mutation resulted from a 588G-A transition. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, GLY170ARG
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000032681, RCV000432954, RCV000589490, RCV003407388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Coulter-Mackie and Rumsby (2004) noted that the gly170-to-arg (G170R) mutation results from a 508G-A (with position 1 being the first coding nucleotide) transition in exon 4 of AGXT. </p><p>Purdue et al. (1990) found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: pro11-to-leu (P11L; 604285.0002), G170R, and ile340-to-met (I340M; 604285.0014). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import. </p><p>Purdue et al. (1991) showed that although the P11L mutation creates a mitochondrial targeting sequence (MTS), the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. </p><p>Salido et al. (2006) showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria. </p><p>In a study of 15 unrelated Italian patients with type I primary hyperoxaluria, Pirulli et al. (1999) found that the most frequent AGXT allele carried the G170R mutation, with a prevalence of 30%. The mutation results from a 630G-A transition. The mutation was found on the background of the minor allele. </p><p>Lumb and Danpure (2000) found that the G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 RECLASSIFIED - ALANINE-GLYOXYLATE AMINOTRANSFERASE POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, ILE340MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs4426527,
|
|
|
|
|
|
gnomAD: rs4426527,
|
|
|
|
|
|
ClinVar: RCV000032682, RCV000247828, RCV001519689
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.</p><p>Coulter-Mackie and Rumsby (2004) noted that the ile340-to-met (I340M) substitution results from a 1020A-G transition exon 10 of AGXT. </p><p>Lumb and Danpure (2000) found that recombinant AGT carrying the P11L (604285.0002) and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HYPEROXALURIA, PRIMARY, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AGXT, 1-BP INS, 33C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177201,
|
|
|
|
|
|
|
|
ClinVar: RCV000128800, RCV000779688, RCV000800941, RCV001849312, RCV003415938, RCV003993816
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Coulter-Mackie and Rumsby (2004) stated that the 33_34insC mutation in exon 1 of the AGXT gene, which occurs on the background of the major allele, is found at a frequency of 12% in affected individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Bourke et al. (1972); Danpure et al. (1987); Danpure (1988); Danpure
|
|
(1993); Purdue et al. (1991); Purdue et al. (1991); Watts et al.
|
|
(1987)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bourke, E., Frindt, G., Flynn, P., Schreiner, G. E.
|
|
<strong>Primary hyperoxaluria with normal alpha-ketoglutarate:glyoxylate carboligase activity: treatment with isocarboxazid.</strong>
|
|
Ann. Intern. Med. 76: 279-284, 1972.
|
|
|
|
|
|
[PubMed: 5009594]
|
|
|
|
|
|
[Full Text: https://doi.org/10.7326/0003-4819-76-2-279]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Caldwell, E. F., Mayor, L. R., Thomas, M. G., Danpure, C. J.
|
|
<strong>Diet and the frequency of the alanine:glyoxylate aminotransferase pro11leu polymorphism in different human populations.</strong>
|
|
Hum. Genet. 115: 504-509, 2004.
|
|
|
|
|
|
[PubMed: 15480793]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-004-1191-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cellini, B., Montioli, R., Paiardini, A., Lorenzetto, A., Voltattorni, C. B.
|
|
<strong>Molecular insight into the synergism between the minor allele of human liver peroxisomal alanine:glyoxylate aminotransferase and the F152I mutation.</strong>
|
|
J. Biol. Chem. 284: 8349-8358, 2009.
|
|
|
|
|
|
[PubMed: 19155213]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M808965200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Coulter-Mackie, M. B., Rumsby, G.
|
|
<strong>Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.</strong>
|
|
Molec. Genet. Metab. 83: 38-46, 2004.
|
|
|
|
|
|
[PubMed: 15464418]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ymgme.2004.08.009]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Danpure, C. J., Jennings, P. R., Watts, R. W. E.
|
|
<strong>Enzymological diagnosis of primary hyperoxaluria type 1 by measurement of hepatic alanine:glyoxylate aminotransferase activity.</strong>
|
|
Lancet 329: 289-291, 1987. Note: Originally Volume I.
|
|
|
|
|
|
[PubMed: 2880111]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0140-6736(87)92023-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Danpure, C. J., Jennings, P. R.
|
|
<strong>Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type I.</strong>
|
|
FEBS Lett. 201: 20-24, 1986.
|
|
|
|
|
|
[PubMed: 3709805]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0014-5793(86)80563-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Danpure, C. J., Purdue, P. E., Fryer, P., Griffiths, S., Allsop, J., Lumb, M. J., Guttridge, K. M., Jennings, P. R., Scheinman, J. I., Mauer, S. M., Davidson, N. O.
|
|
<strong>Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.</strong>
|
|
Am. J. Hum. Genet. 53: 417-432, 1993.
|
|
|
|
|
|
[PubMed: 8101040]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Danpure, C. J.
|
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