2539 lines
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Entry
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- *607198 - TYROSYL-DNA PHOSPHODIESTERASE 1; TDP1
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- OMIM
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<p>
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<span class="h4">*607198</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607198">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<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=ENSG00000042088;t=ENST00000335725" 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=55775" 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=607198" 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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<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=ENSG00000042088;t=ENST00000335725" 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_001008744,NM_001330205,NM_018319,XM_005267848,XM_006720197,XM_011536942,XM_017021440,XM_047431568,XM_047431569,XM_047431570,XM_047431572,XM_047431573,XM_047431574,XM_047431575,XM_047431576,XM_047431577,XM_047431578,XM_047431579,XR_007064032,XR_007064033,XR_007064034,XR_007064035" 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_018319" 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=607198" 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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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06226&isoform_id=06226_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/TDP1" 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/7023536,7648683,7648685,13543875,14035956,15930062,20127586,28071068,37999797,57242805,79154014,85725382,119601820,119601821,119601822,189054943,193785768,530404169,578825950,767980984,1034587518,1056849996,2217297963,2217297967,2217297969,2217297971,2217297974,2217297976,2217297978,2217297981,2217297983,2217297985,2217297987,2462540859,2462540861,2462540863,2462540865,2462540867,2462540869,2462540871,2462540873,2462540875,2462540877,2462540879" 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/Q9NUW8" 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 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=55775" 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=ENSG00000042088;t=ENST00000335725" 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=TDP1" 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=TDP1" 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+55775" 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/TDP1" 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:55775" 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/55775" 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=chr14&hgg_gene=ENST00000335725.9&hgg_start=89954968&hgg_end=90044764&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:18884" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607198[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="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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<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=607198[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/ENSG00000042088" 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=TDP1" 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=TDP1" 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=TDP1" 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=TDP1&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/PA421" 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:18884" 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/FBgn0260817.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:1920036" 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/TDP1#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:1920036" 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/55775/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=55775" 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=WBGene00018678;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-090909-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="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:55775" 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=TDP1&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> 765091006<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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607198
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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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TYROSYL-DNA PHOSPHODIESTERASE 1; TDP1
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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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<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=TDP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TDP1</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/14/451?start=-3&limit=10&highlight=451">14q32.11</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:89954968-90044764&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'})">14:89,954,968-90,044,764</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>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</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">
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<span class="mim-font">
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<a href="/geneMap/14/451?start=-3&limit=10&highlight=451">
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14q32.11
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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">
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?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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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/607250"> 607250 </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">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/607198" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607198" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>Topoisomerases are involved in the replication and readout of the genome. They work by breaking the DNA backbone, allowing a topologic change and the creation of a covalent protein-DNA intermediate union, and resealing the break. This last step is crucial and requires hydrolysis of the DNA-protein bond by a conserved tyrosyl-DNA phosphodiesterase, or TDP (summary by <a href="#4" class="mim-tip-reference" title="Pouliot, J. J., Yao, K. C., Robertson, C. A., Nash, H. A. <strong>Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.</strong> Science 286: 552-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521354</a>] [<a href="https://doi.org/10.1126/science.286.5439.552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521354">Pouliot et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521354" 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 analysis of yeast with disrupted genes after chemical mutagenesis, EST database searching, and 5-prime RACE, <a href="#4" class="mim-tip-reference" title="Pouliot, J. J., Yao, K. C., Robertson, C. A., Nash, H. A. <strong>Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.</strong> Science 286: 552-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521354</a>] [<a href="https://doi.org/10.1126/science.286.5439.552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521354">Pouliot et al. (1999)</a> identified sequences encoding the C- and N-terminal ends of human TDP1. The deduced 608-amino acid protein is highly conserved in eukaryotes, but not, apparently, in prokaryotes. The authors suggested that the gene is a potential tool to enhance the efficacy of anticancer drugs by repairing topoisomerase lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521354" 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 sequence analysis, <a href="#3" class="mim-tip-reference" title="Interthal, H., Pouliot, J. J., Champoux, J. J. <strong>The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily.</strong> Proc. Nat. Acad. Sci. 98: 12009-12014, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11572945[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.211429198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11572945">Interthal et al. (2001)</a> showed that TDP1 contains 2 unusual HKD signature motifs, typical of members of the phospholipase D (PLD; see <a href="/entry/602382">602382</a>) superfamily. Mutation analysis determined that the invariant histidines and lysines of these motifs are essential for TDP1 activity. <a href="#3" class="mim-tip-reference" title="Interthal, H., Pouliot, J. J., Champoux, J. J. <strong>The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily.</strong> Proc. Nat. Acad. Sci. 98: 12009-12014, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11572945[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.211429198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11572945">Interthal et al. (2001)</a> concluded that the hydrolytic reaction catalyzed by TDP1 occurs by the phosphoryl transfer chemistry that is common to all members of the PLD superfamily. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11572945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. <strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong> Nature Genet. 32: 267-272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244316</a>] [<a href="https://doi.org/10.1038/ng987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244316">Takashima et al. (2002)</a> reviewed the function of TDP1. TDP1 is involved in repairing covalent topoisomerase I-DNA complexes and is a member of the phospholipase D superfamily. To modulate the topologic changes induced during DNA replication and transcription, topoisomerase I (TOP1; <a href="/entry/126420">126420</a>) transiently breaks a DNA strand and forms a covalent linkage between the active-site tyrosine and the 3-prime phosphate of the broken DNA strand; the strand is subsequently relegated by nucleophilic attack of the 5-prime hydroxyl on this phosphodiester bond. But under certain conditions, nucleophilic attack of the 5-prime hydroxyl does not occur and the topoisomerase I forms a stalled covalent complex with the DNA. Efficient repair of these stalled complexes requires functional TDP1 to catalyze the hydrolysis of the phosphodiester bond between the tyrosine residue and the DNA 3-prime phosphate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W. <strong>Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.</strong> Nature 434: 108-113, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744309</a>] [<a href="https://doi.org/10.1038/nature03314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744309">El-Khamisy et al. (2005)</a> showed that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 (TOP1; <a href="/entry/126420">126420</a>) activity or oxidative stress. They reported that TDP1 is sequestered into multiprotein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III-alpha (<a href="/entry/600940">600940</a>) and that these complexes are catalytically inactive in lymphoblastoid cell lines derived from patients with spinocerebellar ataxia with axonal neuropathy (SCAN1; <a href="/entry/607250">607250</a>). <a href="#2" class="mim-tip-reference" title="El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W. <strong>Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.</strong> Nature 434: 108-113, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744309</a>] [<a href="https://doi.org/10.1038/nature03314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744309">El-Khamisy et al. (2005)</a> concluded that their data identified a defect in SSBR in a neurodegenerative disease, and implicated this process in the maintenance of genetic integrity in postmitotic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15744309" 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="#1" class="mim-tip-reference" title="Davies, D. R., Interthal, H., Champoux, J. J., Hol, W. G. J. <strong>The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1.</strong> Structure 10: 237-248, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839309</a>] [<a href="https://doi.org/10.1016/s0969-2126(02)00707-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11839309">Davies et al. (2002)</a> resolved the crystal structure of TDP1 at the 1.69-angstrom level. They determined that TDP1 is a monomer composed of 2 similar domains, each contributing his, lys, and asn residues to form a single active site. The structure confirmed that TDP1 has a catalytic mechanism similar to members of the PLD superfamily. <a href="#1" class="mim-tip-reference" title="Davies, D. R., Interthal, H., Champoux, J. J., Hol, W. G. J. <strong>The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1.</strong> Structure 10: 237-248, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839309</a>] [<a href="https://doi.org/10.1016/s0969-2126(02)00707-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11839309">Davies et al. (2002)</a> proposed that the structure indicates how the unusual protein-DNA substrate binds and gives insight into the nature of the substrate in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11839309" 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>In a multigenerational consanguineous Saudi Arabian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; <a href="/entry/607250">607250</a>), <a href="#5" class="mim-tip-reference" title="Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. <strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong> Nature Genet. 32: 267-272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244316</a>] [<a href="https://doi.org/10.1038/ng987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244316">Takashima et al. (2002)</a> identified a homozygous missense mutation in the TDP1 gene (H493R; <a href="#0001">607198.0001</a>). The mutation occurred in the active site of the enzyme, and protein modeling predicted that it would disrupt the symmetric structure of the active site. <a href="#5" class="mim-tip-reference" title="Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. <strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong> Nature Genet. 32: 267-272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244316</a>] [<a href="https://doi.org/10.1038/ng987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244316">Takashima et al. (2002)</a> proposed that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607198[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 1 (1 family)</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">rs119467003 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119467003;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=rs119467003" 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=rs119467003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a multigenerational consanguineous Saudi Arabian family in which 9 members had autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; <a href="/entry/607250">607250</a>), <a href="#5" class="mim-tip-reference" title="Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. <strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong> Nature Genet. 32: 267-272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244316</a>] [<a href="https://doi.org/10.1038/ng987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244316">Takashima et al. (2002)</a> identified a homozygous c.1478A-G transition in the TDP1 gene, resulting in a his493-to-arg (H493R) substitution at a conserved residue in the active site of the enzyme. The mutation was found by linkage analysis followed by candidate gene sequencing. The presenting symptom of this disorder was disturbance of gait in the teen years. There were signs of peripheral axonal motor and sensory neuropathy and distal muscular atrophy with pes cavus and steppage gait. All affected individuals had normal intelligence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244316" 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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Davies, D. R., Interthal, H., Champoux, J. J., Hol, W. G. J.
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<strong>The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1.</strong>
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Structure 10: 237-248, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839309</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11839309" 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/s0969-2126(02)00707-4" target="_blank">Full Text</a>]
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<a id="El-Khamisy2005" class="mim-anchor"></a>
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El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W.
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<strong>Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.</strong>
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Nature 434: 108-113, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744309</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15744309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature03314" target="_blank">Full Text</a>]
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Interthal, H., Pouliot, J. J., Champoux, J. J.
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<strong>The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily.</strong>
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Proc. Nat. Acad. Sci. 98: 12009-12014, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11572945[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=11572945" 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.211429198" target="_blank">Full Text</a>]
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Pouliot, J. J., Yao, K. C., Robertson, C. A., Nash, H. A.
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<strong>Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.</strong>
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Science 286: 552-555, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521354" 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/10.1126/science.286.5439.552" target="_blank">Full Text</a>]
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Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R.
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<strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong>
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Nature Genet. 32: 267-272, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng987" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 2/1/2006
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Paul J. Converse : 9/5/2002
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 04/15/2019
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ckniffin : 04/15/2019<br>carol : 12/29/2011<br>alopez : 2/2/2006<br>terry : 2/1/2006<br>terry : 1/2/2003<br>alopez : 12/18/2002<br>alopez : 9/24/2002<br>alopez : 9/24/2002<br>mgross : 9/5/2002
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<strong>*</strong> 607198
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TYROSYL-DNA PHOSPHODIESTERASE 1; TDP1
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<strong><em>HGNC Approved Gene Symbol: TDP1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 765091006;
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Cytogenetic location: 14q32.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:89,954,968-90,044,764 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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<span class="mim-font">
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?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
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<span class="mim-font">
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607250
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<p>Topoisomerases are involved in the replication and readout of the genome. They work by breaking the DNA backbone, allowing a topologic change and the creation of a covalent protein-DNA intermediate union, and resealing the break. This last step is crucial and requires hydrolysis of the DNA-protein bond by a conserved tyrosyl-DNA phosphodiesterase, or TDP (summary by Pouliot et al., 1999). </p>
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<strong>Cloning and Expression</strong>
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<p>By analysis of yeast with disrupted genes after chemical mutagenesis, EST database searching, and 5-prime RACE, Pouliot et al. (1999) identified sequences encoding the C- and N-terminal ends of human TDP1. The deduced 608-amino acid protein is highly conserved in eukaryotes, but not, apparently, in prokaryotes. The authors suggested that the gene is a potential tool to enhance the efficacy of anticancer drugs by repairing topoisomerase lesions. </p><p>By sequence analysis, Interthal et al. (2001) showed that TDP1 contains 2 unusual HKD signature motifs, typical of members of the phospholipase D (PLD; see 602382) superfamily. Mutation analysis determined that the invariant histidines and lysines of these motifs are essential for TDP1 activity. Interthal et al. (2001) concluded that the hydrolytic reaction catalyzed by TDP1 occurs by the phosphoryl transfer chemistry that is common to all members of the PLD superfamily. </p>
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<strong>Gene Function</strong>
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<p>Takashima et al. (2002) reviewed the function of TDP1. TDP1 is involved in repairing covalent topoisomerase I-DNA complexes and is a member of the phospholipase D superfamily. To modulate the topologic changes induced during DNA replication and transcription, topoisomerase I (TOP1; 126420) transiently breaks a DNA strand and forms a covalent linkage between the active-site tyrosine and the 3-prime phosphate of the broken DNA strand; the strand is subsequently relegated by nucleophilic attack of the 5-prime hydroxyl on this phosphodiester bond. But under certain conditions, nucleophilic attack of the 5-prime hydroxyl does not occur and the topoisomerase I forms a stalled covalent complex with the DNA. Efficient repair of these stalled complexes requires functional TDP1 to catalyze the hydrolysis of the phosphodiester bond between the tyrosine residue and the DNA 3-prime phosphate. </p><p>El-Khamisy et al. (2005) showed that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 (TOP1; 126420) activity or oxidative stress. They reported that TDP1 is sequestered into multiprotein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III-alpha (600940) and that these complexes are catalytically inactive in lymphoblastoid cell lines derived from patients with spinocerebellar ataxia with axonal neuropathy (SCAN1; 607250). El-Khamisy et al. (2005) concluded that their data identified a defect in SSBR in a neurodegenerative disease, and implicated this process in the maintenance of genetic integrity in postmitotic neurons. </p>
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<strong>Biochemical Features</strong>
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<p>Davies et al. (2002) resolved the crystal structure of TDP1 at the 1.69-angstrom level. They determined that TDP1 is a monomer composed of 2 similar domains, each contributing his, lys, and asn residues to form a single active site. The structure confirmed that TDP1 has a catalytic mechanism similar to members of the PLD superfamily. Davies et al. (2002) proposed that the structure indicates how the unusual protein-DNA substrate binds and gives insight into the nature of the substrate in vivo. </p>
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<strong>Molecular Genetics</strong>
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<p>In a multigenerational consanguineous Saudi Arabian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; 607250), Takashima et al. (2002) identified a homozygous missense mutation in the TDP1 gene (H493R; 607198.0001). The mutation occurred in the active site of the enzyme, and protein modeling predicted that it would disrupt the symmetric structure of the active site. Takashima et al. (2002) proposed that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons. </p>
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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>1 Selected Example):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 1 (1 family)</strong>
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</h4>
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<span class="mim-text-font">
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TDP1, HIS493ARG
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<br />
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SNP: rs119467003,
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ClinVar: RCV000003593, RCV003128568
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<p>In a multigenerational consanguineous Saudi Arabian family in which 9 members had autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1; 607250), Takashima et al. (2002) identified a homozygous c.1478A-G transition in the TDP1 gene, resulting in a his493-to-arg (H493R) substitution at a conserved residue in the active site of the enzyme. The mutation was found by linkage analysis followed by candidate gene sequencing. The presenting symptom of this disorder was disturbance of gait in the teen years. There were signs of peripheral axonal motor and sensory neuropathy and distal muscular atrophy with pes cavus and steppage gait. All affected individuals had normal intelligence. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Davies, D. R., Interthal, H., Champoux, J. J., Hol, W. G. J.
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<strong>The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1.</strong>
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Structure 10: 237-248, 2002.
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[PubMed: 11839309]
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[Full Text: https://doi.org/10.1016/s0969-2126(02)00707-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W.
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<strong>Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.</strong>
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Nature 434: 108-113, 2005.
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[PubMed: 15744309]
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[Full Text: https://doi.org/10.1038/nature03314]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Interthal, H., Pouliot, J. J., Champoux, J. J.
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<strong>The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily.</strong>
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Proc. Nat. Acad. Sci. 98: 12009-12014, 2001.
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[PubMed: 11572945]
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[Full Text: https://doi.org/10.1073/pnas.211429198]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Pouliot, J. J., Yao, K. C., Robertson, C. A., Nash, H. A.
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<strong>Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.</strong>
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Science 286: 552-555, 1999.
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[PubMed: 10521354]
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[Full Text: https://doi.org/10.1126/science.286.5439.552]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R.
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|
<strong>Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.</strong>
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Nature Genet. 32: 267-272, 2002.
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[PubMed: 12244316]
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[Full Text: https://doi.org/10.1038/ng987]
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</p>
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</li>
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</ol>
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<span class="text-nowrap mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 2/1/2006
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 9/5/2002
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</span>
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Edit History:
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carol : 04/15/2019<br>ckniffin : 04/15/2019<br>carol : 12/29/2011<br>alopez : 2/2/2006<br>terry : 2/1/2006<br>terry : 1/2/2003<br>alopez : 12/18/2002<br>alopez : 9/24/2002<br>alopez : 9/24/2002<br>mgross : 9/5/2002
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