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<title>
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Entry
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- *608700 - NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1
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- OMIM
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<div class="row">
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<div class="row">
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<p>
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<span class="h4">*608700</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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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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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608700">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000173614;t=ENST00000377205" 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=64802" 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=608700" 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="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000173614;t=ENST00000377205" 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_001297778,NM_001297779,NM_022787,XM_011541971,XM_017002107,XM_017002108,XM_047428076,XM_047428077,XM_047428080,XM_047428082" 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_022787" 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=608700" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=16369&isoform_id=16369_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/NMNAT1" 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/10438792,11245472,11245478,15928950,18652051,18652057,20070321,30580491,62897399,108250318,119592041,119592042,122346666,189055023,545685830,663071195,663071197,767905615,1034561127,1034561129,2217270187,2217270190,2217270192,2217270194,2462512718,2462512720,2462512722,2462512724,2462512726,2462512728,2462512730" 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/Q9HAN9" 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=64802" 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=ENSG00000173614;t=ENST00000377205" 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=NMNAT1" 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=NMNAT1" 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+64802" 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/NMNAT1" 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:64802" 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/64802" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000377205.6&hgg_start=9942923&hgg_end=9996892&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:17877" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608700[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=608700[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/ENSG00000173614" 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=NMNAT1" 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=NMNAT1" 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=NMNAT1" 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=NMNAT1&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/PA31660" 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:17877" 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/FBgn0039254.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:1913704" 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/NMNAT1#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:1913704" 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/64802/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=64802" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00009176;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00009176 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00012295;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00012295 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-050417-101" 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:64802" 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=NMNAT1&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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</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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608700
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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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NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1
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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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NMNAT<br />
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PYRIDINE NUCLEOTIDE ADENYLYLTRANSFERASE 1; PNAT1
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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=NMNAT1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NMNAT1</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/1/132?start=-3&limit=10&highlight=132">1p36.22</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:9942923-9996892&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:9,942,923-9,996,892</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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Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<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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<p>The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca(2+) signaling pathways. NMNAT (<a href="https://enzyme.expasy.org/EC/2.7.7.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.7.7.1</a>) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD (<a href="#22" class="mim-tip-reference" title="Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., Zhang, H. <strong>Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis.</strong> J. Biol. Chem. 278: 13503-13511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12574164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12574164</a>] [<a href="https://doi.org/10.1074/jbc.M300073200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12574164">Zhang et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12574164" 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 searching an EST database for sequences similar to peptide fragments of NMNAT1 purified from placenta, followed by PCR of a placenta cDNA library, <a href="#7" class="mim-tip-reference" title="Emanuelli, M., Carnevali, F., Saccucci, F., Pierella, F., Amici, A., Raffaelli, N., Magni, G. <strong>Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase.</strong> J. Biol. Chem. 276: 406-412, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027696</a>] [<a href="https://doi.org/10.1074/jbc.M008700200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027696">Emanuelli et al. (2001)</a> cloned NMNAT1. The deduced 279-amino acid protein has a calculated molecular mass of 31.9 kD. It contains a conserved N-terminal adenylyltransferase motif, an N-terminal N-glycosylation site, and several potential transmembrane regions. Northern blot analysis detected 3.1- and 4.1-kb transcripts expressed at variable levels in all tissues examined. The 3.1-kb transcript was more abundant, and expression was highest in skeletal muscle, heart, liver, and kidney; thymus and spleen showed a weak signal. Expression was reduced in all tumor cell lines examined except in a lymphoma cell line and a chronic myelogenous leukemia cell line. Purified recombinant NMNAT1 migrated with an apparent molecular mass of 33 kD by SDS-PAGE. Gel filtration analysis detected active recombinant enzyme at an apparent molecular mass of 139 kD, suggesting that NMNAT1 forms a homotetramer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Schweiger, M., Hennig, K., Lerner, F., Niere, M., Hirsch-Kauffmann, M., Specht, T., Weise, C., Oei, S. L., Ziegler, M. <strong>Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis.</strong> FEBS Lett. 492: 95-100, 2001. Note: Erratum: FEBS Lett. 496: 68 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248244</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02180-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248244">Schweiger et al. (2001)</a> cloned NMNAT1 from a lymphoblastoid cell cDNA library. The deduced protein contains an N-terminal nuclear localization signal. Immunofluorescence microscopy localized endogenous NMNAT1 to the nucleus in human fibroblasts and in a hepatoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Fernando, F. S., Conforti, L., Tosi, S., Smith, A. D., Coleman, M. P. <strong>Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse.</strong> Gene 284: 23-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11891043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11891043</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)00394-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11891043">Fernando et al. (2002)</a> determined that the human and mouse NMNAT1 proteins share 78.4% amino acid identity. Northern blot analysis detected an abundant 3.1-kb transcript and a less abundant 4.1-kb transcript in skeletal muscle, heart, and all brain regions examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11891043" 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 immunofluorescence analysis, <a href="#5" class="mim-tip-reference" title="Berger, F., Lau, C., Dahlmann, M., Ziegler, M. <strong>Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms.</strong> J. Biol. Chem. 280: 36334-36341, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16118205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16118205</a>] [<a href="https://doi.org/10.1074/jbc.M508660200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16118205">Berger et al. (2005)</a> showed that fluorescence-tagged NMNAT1 localized exclusively within nuclei of transfected HeLa and HEK293 cells, similar to the endogenous protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16118205" 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 addition to canonical isoform 1 of NMNAT1 and alternative isoform 2, <a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> identified a third isoform present in healthy human tissues. Levels of expression were highest for isoform 1 in all tissues tested, followed by isoform 2; novel isoform 3 presented lower levels of expression, but was always detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" 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 an Nmnat1-lacZ fusion protein lacking the nuclear localization signal, <a href="#17" class="mim-tip-reference" title="Sasaki, Y., Kakita, H., Kubota, S., Sene, A., Lee, T. J., Ban, N., Dong, Z., Lin, J. B., Boye, S. L., DiAntonio, A., Boye, S. E., Apte, R. S., Milbrandt, J. <strong>SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.</strong> eLife 9: e62027, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33107823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33107823</a>] [<a href="https://doi.org/10.7554/eLife.62027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33107823">Sasaki et al. (2020)</a> showed that Nmnat1 was ubiquitously expressed in mouse retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33107823" 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="#9" class="mim-tip-reference" title="Fernando, F. S., Conforti, L., Tosi, S., Smith, A. D., Coleman, M. P. <strong>Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse.</strong> Gene 284: 23-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11891043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11891043</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)00394-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11891043">Fernando et al. (2002)</a> determined that the NMNAT1 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11891043" 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 FISH, <a href="#7" class="mim-tip-reference" title="Emanuelli, M., Carnevali, F., Saccucci, F., Pierella, F., Amici, A., Raffaelli, N., Magni, G. <strong>Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase.</strong> J. Biol. Chem. 276: 406-412, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027696</a>] [<a href="https://doi.org/10.1074/jbc.M008700200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027696">Emanuelli et al. (2001)</a> mapped the NMNAT1 gene to chromosome 1p35-p32. Southern blot analysis indicated that NMNAT1 is a single-copy gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027696" 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 FISH, <a href="#9" class="mim-tip-reference" title="Fernando, F. S., Conforti, L., Tosi, S., Smith, A. D., Coleman, M. P. <strong>Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse.</strong> Gene 284: 23-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11891043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11891043</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)00394-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11891043">Fernando et al. (2002)</a> mapped the NMNAT1 gene to chromosome 1p36.2 in a region that shows homology of synteny to distal mouse chromosome 4. FISH and genomic sequence analyses identified several NMNAT1 homologs on chromosomes 3, 4, 14, and 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11891043" 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="#23" class="mim-tip-reference" title="Zhou, T., Kurnasov, O., Tomchick, D. R., Binns, D. D., Grishin, N. V., Marquez, V. E., Osterman, A. L., Zhang, H. <strong>Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase: basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.</strong> J. Biol. Chem. 277: 13148-13154, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788603</a>] [<a href="https://doi.org/10.1074/jbc.M111469200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788603">Zhou et al. (2002)</a> solved the crystal structures of NMNAT1 in complex with NAD, deamido-NAD, and a nonhydrolyzable analog of the anticancer drug tiazofurin. The structures suggested a mechanism for the broad substrate specificity of the enzyme toward both NMN and NaMN and for adenylation of tiazofurin nucleotide. The crystal structure also showed that NMNAT1 forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role in interacting with nuclear transporting proteins. Analytic ultracentrifugation results were consistent with the formation of a hexamer in solution under certain conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Emanuelli, M., Carnevali, F., Saccucci, F., Pierella, F., Amici, A., Raffaelli, N., Magni, G. <strong>Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase.</strong> J. Biol. Chem. 276: 406-412, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027696</a>] [<a href="https://doi.org/10.1074/jbc.M008700200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027696">Emanuelli et al. (2001)</a> confirmed that recombinant NMNAT1 exhibited adenylyltransferase activity, converting NMN to NAD in the presence of ATP. When deamido-NMN was used as the substrate, the rate of reaction was comparable to that for NMN, but the K(m) was higher, suggesting that the amido pathway is predominant. NMNAT1 had an absolute requirement for divalent cations, with optimum activity with 12 mM Mg(2+), and activity was depressed by several heavy metal ions. NMNAT1 also showed a broad pH optimum, ranging from pH 6.0 to 8.0, similar to NMNAT purified from other species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Schweiger, M., Hennig, K., Lerner, F., Niere, M., Hirsch-Kauffmann, M., Specht, T., Weise, C., Oei, S. L., Ziegler, M. <strong>Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis.</strong> FEBS Lett. 492: 95-100, 2001. Note: Erratum: FEBS Lett. 496: 68 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248244</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02180-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248244">Schweiger et al. (2001)</a> demonstrated that NMNAT1 inhibited recombinant human poly(ADP-ribose) polymerase-1 (ADPRT; <a href="/entry/173870">173870</a>) by about 35%, and it completely prevented the formation of branched ADP-ribose polymers. NMNAT1 was not itself an acceptor protein for ADP-ribosylation. Incubation with nuclear extracts resulted in phosphorylation of recombinant NMNAT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248244" 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 Wallerian degeneration slow (wld-s) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wld-s) composed of the ubiquitin assembly protein Ufd2a (<a href="/entry/603753">603753</a>) and Nmnat1. <a href="#2" class="mim-tip-reference" title="Araki, T., Sasaki, Y., Milbrandt, J. <strong>Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.</strong> Science 305: 1010-1013, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15310905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15310905</a>] [<a href="https://doi.org/10.1126/science.1098014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15310905">Araki et al. (2004)</a> demonstrated that increased Nmnat activity is responsible for the axon-sparing activity of the Wld-s protein. Furthermore, they demonstrated that Sirt1 (<a href="/entry/604479">604479</a>) is the downstream effector of increased Nmnat activity that leads to axonal protection. <a href="#2" class="mim-tip-reference" title="Araki, T., Sasaki, Y., Milbrandt, J. <strong>Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.</strong> Science 305: 1010-1013, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15310905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15310905</a>] [<a href="https://doi.org/10.1126/science.1098014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15310905">Araki et al. (2004)</a> concluded that novel therapeutic strategies directed at increasing the supply of NAD and/or SIR2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15310905" 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 purified recombinant proteins, <a href="#5" class="mim-tip-reference" title="Berger, F., Lau, C., Dahlmann, M., Ziegler, M. <strong>Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms.</strong> J. Biol. Chem. 280: 36334-36341, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16118205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16118205</a>] [<a href="https://doi.org/10.1074/jbc.M508660200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16118205">Berger et al. (2005)</a> compared the enzymatic properties of NMNAT1, NMNAT2 (<a href="/entry/608701">608701</a>), and NMNAT3 (<a href="/entry/608702">608702</a>). NMNAT3 exhibited a high tolerance for substrate modifications. In contrast with the preferred NAD+ synthesis by NMNAT1, NMNAT2 and NMNAT3 could also form NADH directly from the reduced nicotinamide mononucleotide. A variety of physiologic intermediates had only minor influence on NMNAT catalytic activity. However, gallotannin was a potent inhibitor of NMNAT catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16118205" 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>Studies in Drosophila (see ANIMAL MODEL) have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase against activity-induced neurodegeneration and injury-induced axonal degeneration (<a href="#20" class="mim-tip-reference" title="Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., Bellen, H. J. <strong>Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.</strong> PLoS Biol. 4: e416, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17132048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17132048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17132048[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/10.1371/journal.pbio.0040416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17132048">Zhai et al., 2006</a>, <a href="#14" class="mim-tip-reference" title="MacDonald, J. M., Beach, M. G., Porpiglia, E., Sheehan, A. E., Watts, R. J., Freeman, M. R. <strong>The Drosophila cell corpse engulfment receptor draper mediates glial clearance of severed axons.</strong> Neuron 50: 869-881, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16772169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16772169</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.04.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16772169">MacDonald et al., 2006</a>). <a href="#21" class="mim-tip-reference" title="Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., Bellen, H. J. <strong>NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.</strong> Nature 452: 887-891, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18344983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18344983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18344983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18344983">Zhai et al. (2008)</a> showed that NMNAT overexpression can also protect against ataxin (<a href="/entry/601556">601556</a>)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein-70 (HSP70; <a href="/entry/140550">140550</a>). NMNAT displayed chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of polyglutamine-expanded protein and recruited with the chaperone Hsp70 into protein aggregates. <a href="#21" class="mim-tip-reference" title="Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., Bellen, H. J. <strong>NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.</strong> Nature 452: 887-891, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18344983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18344983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18344983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18344983">Zhai et al. (2008)</a> concluded that their results implicated NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16772169+17132048+18344983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Leber Congenital Amaurosis 9</em></strong></p><p>
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In 8 families with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified homozygosity or compound heterozygosity for missense mutations in the NMNAT1 gene (see, e.g., <a href="#0001">608700.0001</a>-<a href="#0007">608700.0007</a>) that segregated with disease in each family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" 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 11 probands with severe LCA, <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> identified compound heterozygosity for missense and/or nonsense mutations in the NMNAT1 gene (see, e.g., <a href="#0002">608700.0002</a>-<a href="#0004">608700.0004</a> and <a href="#0006">608700.0006</a>). The most common variant, E257K (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150726175;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs150726175</a>; <a href="#0002">608700.0002</a>), was present as 1 of 2 variant alleles in all 11 probands and was estimated to have an allele frequency of 0.001. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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 affected individuals from 14 families with severe LCA, <a href="#8" class="mim-tip-reference" title="Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others. <strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong> Nature Genet. 44: 1040-1045, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842227">Falk et al. (2012)</a> identified homozygosity or compound heterozygosity for missense and/or frameshift mutations in the NMNAT1 gene (see, e.g., <a href="#0009">608700.0009</a>), including 6 patients who carried the E257K mutation on 1 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842227" 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 22 of 261 LCA probands without mutations in known LCA genes, <a href="#16" class="mim-tip-reference" title="Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong> Nature Genet. 44: 975-977, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842229</a>] [<a href="https://doi.org/10.1038/ng.2357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842229">Perrault et al. (2012)</a> identified homozygosity (<a href="#0006">608700.0006</a>) or compound heterozygosity for mutations in the NMNAT1 gene (see, e.g., <a href="#0002">608700.0002</a> and <a href="#0005">608700.0005</a>). In 7 probands, only a single heterozygous NMNAT1 mutation was found, but because they presented an identical phenotype to that of patients in whom 2 mutations were identified it was likely that they harbored a second undetected NMNAT1 mutant allele. The most common mutation detected was the E257K variant, which was present on 1 allele in 23 of the 29 index cases with mutation in NMNAT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Arab sister and brother with early-onset retinal dystrophy with central nummular macular atrophy, <a href="#11" class="mim-tip-reference" title="Khan, A. O., Budde, B. S., Nurnberg, P., Kawalia, A., Lenzner, S., Bolz, H. J. <strong>Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.</strong> Clin. Genet. 93: 149-154, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369829</a>] [<a href="https://doi.org/10.1111/cge.13022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28369829">Khan et al. (2018)</a> identified homozygosity for a missense mutation in the NMNAT1 gene (N167S; <a href="#0012">608700.0012</a>) that segregated with disease in the family and was not found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28369829" 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 26-year-old Indian woman with early-onset retinal dystrophy and coloboma-like macular atrophy, <a href="#15" class="mim-tip-reference" title="Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V. <strong>NMNAT1 variants cause cone and cone-rod dystrophy.</strong> Europ. J. Hum. Genet. 26: 428-433, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29184169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29184169</a>] [<a href="https://doi.org/10.1038/s41431-017-0029-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29184169">Nash et al. (2018)</a> identified homozygosity for a missense mutation in the NMNAT1 gene (E91K; <a href="#0013">608700.0013</a>). A similarly affected 14-year-old Caucasian girl was found to be compound heterozygous for the common E257K variant and another missense mutation in the NMNAT1 gene (N18S; <a href="#0014">608700.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29184169" 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>From a Spanish cohort of 76 patients with LCA or early-onset retinal dystrophy, <a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> identified a 6-year-old boy with LCA who was compound heterozygous for the common E257K variant and a 7.4-bp duplication within the NMNAT1 gene (<a href="#0010">608700.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Egyptian brother and sister with early-onset progressive retinal dysfunction with foveal hypoplasia, <a href="#4" class="mim-tip-reference" title="Bedoukian, E. C., Zhu, X., Serrano, L. E., Scoles, D., Aleman, T. S. <strong>NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment.</strong> Retin. Cases Brief Rep. 4Mar, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32150116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32150116</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32150116">Bedoukian et al. (2020)</a> identified compound heterozygous mutations in the NMNAT1 gene: the E257K variant and another missense mutation (V82L; <a href="#0015">608700.0015</a>). The authors concluded that NMNAT1 mutations cause a consistent phenotype characterized by early-onset progressive retina-wide dysfunction, affecting cones more than rods, with predominantly central abnormalities ranging from hypoplasia to atrophy of the fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32150116" 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 sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, <a href="#13" class="mim-tip-reference" title="Kumaran, N., Robson, A. G., Michaelides, M. <strong>A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum.</strong> Retin. Cases Brief Rep. 15: 139-144, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30004997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30004997</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30004997">Kumaran et al. (2021)</a> identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene, noting that these cases extended the phenotypic spectrum associated with the NMNAT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30004997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis</em></strong></p><p>
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In an Italian brother and sister and an unrelated Italian boy with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; <a href="/entry/619260">619260</a>), <a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> identified homozygosity for a 7.4-kb duplication within the NMNAT1 gene (<a href="#0010">608700.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2-year-old Spanish girl with SHILCA syndrome, <a href="#1" class="mim-tip-reference" title="Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. <strong>New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform.</strong> Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33668384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33668384</a>] [<a href="https://doi.org/10.3390/ijms22052262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33668384">Abad-Morales et al. (2021)</a> identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation in the NMNAT1 gene (<a href="#0011">608700.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33668384" 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="#20" class="mim-tip-reference" title="Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., Bellen, H. J. <strong>Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.</strong> PLoS Biol. 4: e416, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17132048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17132048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17132048[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/10.1371/journal.pbio.0040416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17132048">Zhai et al. (2006)</a> found that knockdown of Nmnat in Drosophila resulted in retinal neurodegeneration that was exacerbated by neural activity. Neurodegeneration was independent of apoptosis. Overexpression of an inactive Nmnat mutant protected mutant retinas from activity-induced neurodegeneration, suggesting a dual role for Nmnat in NAD synthesis and in maintaining neuronal integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17132048" 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>Studying glaucoma-prone mice (the DBA/2J strain), <a href="#19" class="mim-tip-reference" title="Williams, P. A., Harder, J. M., Foxworth, N. E., Cichran, K. E., Philip, V. M., Porciatti, V., Smithies, O., John, S. W. M. <strong>Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.</strong> Science 355: 756-760, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28209901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28209901</a>] [<a href="https://doi.org/10.1126/science.aal0092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28209901">Williams et al. (2017)</a> showed that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults, including increased intraocular pressure. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD(+)-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. <a href="#19" class="mim-tip-reference" title="Williams, P. A., Harder, J. M., Foxworth, N. E., Cichran, K. E., Philip, V. M., Porciatti, V., Smithies, O., John, S. W. M. <strong>Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.</strong> Science 355: 756-760, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28209901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28209901</a>] [<a href="https://doi.org/10.1126/science.aal0092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28209901">Williams et al. (2017)</a> concluded that their results supported therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28209901" 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="Sasaki, Y., Kakita, H., Kubota, S., Sene, A., Lee, T. J., Ban, N., Dong, Z., Lin, J. B., Boye, S. L., DiAntonio, A., Boye, S. E., Apte, R. S., Milbrandt, J. <strong>SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.</strong> eLife 9: e62027, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33107823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33107823</a>] [<a href="https://doi.org/10.7554/eLife.62027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33107823">Sasaki et al. (2020)</a> noted that knockout of Nmnat1 in mice is embryonic lethal. They found that conditional knockout of Nmnat1 in 2-month-old mice induced loss of photoreceptor cells and inhibited retinal function, leading to severe retinal degeneration. Photoreceptor-specific depletion of Nmnat1 also resulted in retinal degeneration, which could be partially rescued by transgenic expression of Nmnat1. Further analysis demonstrated that loss of Nmnat1 in photoreceptors activated Sarm1 (<a href="/entry/607732">607732</a>), and that Sarm1 was required for subsequent photoreceptor degeneration and loss of visual function. Consequently, depletion of Sarm1 rescued retinal degeneration in Nmnat1-deficient retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33107823" 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 affected members of a large consanguineous Pakistani family with Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), originally reported by <a href="#10" class="mim-tip-reference" title="Keen, T. J., Mohamed, M. D., McKibbin, M., Rashid, Y., Jafri, H., Maumenee, I. H., Inglehearn, C. F. <strong>Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36.</strong> Europ. J. Hum. Genet. 11: 420-423, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12734549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12734549</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12734549">Keen et al. (2003)</a>, <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified homozygosity for an 838T-C transition in the NMNAT1 gene, resulting in a ter280-to-gln (X280Q) substitution that was predicted to elongate the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22842230+12734549" 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> rs150726175 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150726175;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/rs150726175?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=rs150726175" 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=rs150726175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 probands with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified a 769G-A transition in exon 5 of the NMNAT1 gene, resulting in a glu257-to-lys (E257K) substitution at a conserved residue in a protein-interaction domain interface, predicted to interfere with hexamer formation. The mutation was found in homozygosity in 1 proband, and was present in compound heterozygosity with another missense mutation in the NMNAT1 gene in the other 4 probands (see, e.g., <a href="#0003">608700.0003</a>-<a href="#0005">608700.0005</a>). All mutations segregated with disease in each family and were not found in 200 controls. In red blood cells (RBCs) from the patient homozygous for E257K there was a significantly lower concentration of NAD compared with that in RBCs from his heterozygous mother, suggesting reduced enzymatic function of the mutant protein. Immunohistochemical studies in transfected HeLa cells demonstrated that whereas wildtype NMNAT1 showed strong nuclear staining, the E257K mutant stained strongly outside of the cell nucleus in the cytoplasm; in addition, the mutant protein was positive for ubiquitin staining, indicating that the mutation likely affects protein folding. In vitro assay showed significantly reduced enzymatic activity with the E257K mutant protein compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" 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 11 probands with severe LCA, <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> identified compound heterozygosity for the E257K mutation and another missense or nonsense mutation in the NMNAT1 gene (see, e.g., N273D, <a href="#0003">608700.0003</a>; V151F, <a href="#0004">608700.0004</a>; and W169X, <a href="#0006">608700.0006</a>). <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> stated that the allele frequency of E257K (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150726175;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs150726175</a>) was estimated to be 0.001, whereas the remainder of the variants had not been reported in any public database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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 6 probands with LCA, <a href="#8" class="mim-tip-reference" title="Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others. <strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong> Nature Genet. 44: 1040-1045, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842227">Falk et al. (2012)</a> identified compound heterozygosity for the E257K mutation and another missense or frameshift mutation in the NMNAT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842227" 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="#16" class="mim-tip-reference" title="Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong> Nature Genet. 44: 975-977, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842229</a>] [<a href="https://doi.org/10.1038/ng.2357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842229">Perrault et al. (2012)</a> identified the E257K variant on 1 allele in 23 of 29 probands with LCA in whom mutation in NMNAT1 was detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842229" 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 6-year-old Spanish boy with LCA, <a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> identified compound heterozygosity for the E257K variant and a 7.4-kb duplication within the NMNAT1 gene (<a href="#0010">608700.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" 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 14-year-old Caucasian girl (case 2) with early-onset retinal dystrophy and coloboma-like macular atrophy, <a href="#15" class="mim-tip-reference" title="Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V. <strong>NMNAT1 variants cause cone and cone-rod dystrophy.</strong> Europ. J. Hum. Genet. 26: 428-433, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29184169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29184169</a>] [<a href="https://doi.org/10.1038/s41431-017-0029-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29184169">Nash et al. (2018)</a> identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.53A-G transition, resulting in an asn18-to-ser (N18S; <a href="#0014">608700.0014</a>) substitution. The N18S variant was present in 5 of 276,912 alleles in the gnomAD database (minor allele frequency, 0.000018). The authors noted that ERG findings in this patient showed reduced photopic and scotopic responses, consistent with cone-rod dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29184169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia, consistent with cone-rod dystrophy, <a href="#4" class="mim-tip-reference" title="Bedoukian, E. C., Zhu, X., Serrano, L. E., Scoles, D., Aleman, T. S. <strong>NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment.</strong> Retin. Cases Brief Rep. 4Mar, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32150116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32150116</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32150116">Bedoukian et al. (2020)</a> identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.245T-C transition, resulting in a val82-to-ala (V82A; <a href="#0015">608700.0015</a>) substitution. Their unaffected parents were each heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32150116" 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 sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, <a href="#13" class="mim-tip-reference" title="Kumaran, N., Robson, A. G., Michaelides, M. <strong>A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum.</strong> Retin. Cases Brief Rep. 15: 139-144, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30004997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30004997</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30004997">Kumaran et al. (2021)</a> identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene. Their unaffected parents were each heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30004997" 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 56-year-old French Canadian woman with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified compound heterozygosity for an 817A-G transition in exon 5 of the NMNAT1 gene, resulting in an asn273-to-asp (N273D) substitution at a conserved residue, and an E257K substitution (<a href="#0002">608700.0002</a>). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 8-year-old Canadian boy of western European ancestry who had severe LCA, <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> identified compound heterozygosity for the N273D and E257K mutations in the NMNAT1 gene. The E257K and N273D mutations were inherited from his unaffected mother and father, respectively, and a third mutation was detected on the paternal allele as well: a 457C-G transversion in the NMNAT1 gene, resulting in a leu153-to-val (L153V; <a href="#0008">608700.0008</a>) substitution near the site of ligand binding, predicted to disturb local interactions and affect enzymatic activity. At 7 years of age, ERG showed primarily cone dysfunction rather than profound loss of all responses, and the patient's diagnosis was revised from 'variant LCA' to 'cone-rod dystrophy.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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 European female with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified compound heterozygosity for a 451G-A transition in exon 5 of the NMNAT1 gene, resulting in a val151-to-phe (V151F) substitution at a conserved residue in the adenylyltransferase domain, and an E257K substitution (<a href="#0002">608700.0002</a>). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" 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 26-year-old Canadian man of Greek ancestry with severe LCA, <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> identified compound heterozygosity for the V151F and E257K mutations in the NMNAT1 gene. At 6 months of age, the patient was diagnosed with retinitis pigmentosa (see <a href="/entry/268000">268000</a>), but the diagnosis was later changed to LCA. Major vision loss occurred around 18 years of age, with colors and shapes still seen at age 20, at which time he began using a guide dog. Colors and shapes were lost at 22 years and 24 years of age, respectively, and by 26 years of age, the patient could only distinguish between light and dark. Eye examination showed wandering eye movements, macular atrophic lesions, attenuated vessels, and bone spicule pigmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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> rs142968179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs142968179;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/rs142968179?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=rs142968179" 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=rs142968179" 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 13-year-old French Canadian boy with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified compound heterozygosity for a 619C-T transition in exon 5 of the NMNAT1 gene, resulting in an arg207-to-trp (R207W) substitution in the adenylyltransferase domain, and an E257K substitution (<a href="#0002">608700.0002</a>). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" 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 7 unrelated probands with LCA, <a href="#16" class="mim-tip-reference" title="Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong> Nature Genet. 44: 975-977, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842229</a>] [<a href="https://doi.org/10.1038/ng.2357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842229">Perrault et al. (2012)</a> identified compound heterozygosity for the R207W and E257K mutations in the NMNAT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842229" 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> rs371526758 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371526758;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/rs371526758?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=rs371526758" 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=rs371526758" 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 33-year-old Irish woman with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a> identified compound heterozygosity for a 507G-A transition in exon 5 of the NMNAT1 gene, resulting in a trp169-to-ter (W169X) substitution, and a 710G-T transversion in exon 5, resulting in an arg237-to-leu (R237L; <a href="#0007">608700.0007</a>) substitution, both at conserved residues in the adenylyltransferase domain. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 200 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 probands with severe LCA, <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> identified compound heterozygosity for the W169X and E257K (<a href="#0002">608700.0002</a>) mutations in the NMNAT1 gene. <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a> noted that these patients who carried the nonsense mutation W169X in combination with E257K were all blind at birth and had only varying degrees of light perception still present, whereas 5 patients who carried various missense mutations in combination with E257K had vision that decreased within a few years after birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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 16-year-old girl with LCA who was born of consanguineous Algerian parents, <a href="#16" class="mim-tip-reference" title="Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong> Nature Genet. 44: 975-977, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842229</a>] [<a href="https://doi.org/10.1038/ng.2357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842229">Perrault et al. (2012)</a> identified homozygosity for the W169X mutation in the NMNAT1 gene. Her unaffected parents and sister were heterozygous for the mutation, which was not found in 200 controls. The patient had high hyperopia, night blindness, visual acuity at the level of counting fingers since 4 years of age, and macular alteration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the arg273-to-leu (R273L) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>) by <a href="#12" class="mim-tip-reference" title="Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others. <strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong> Nature Genet. 44: 1035-1039, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842230">Koenekoop et al. (2012)</a>, see <a href="#0006">608700.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842230" 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> rs387907293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907293;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/rs387907293?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=rs387907293" 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=rs387907293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the leu153-to-val (L153V) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>) by <a href="#6" class="mim-tip-reference" title="Chiang, P.-W., Wang, J., Chen, Y., Fu, Q., Zhong, J., Chen, Y., Yi, X., Wu, R., Gan, H., Shi, Y., Chen, Y., Barnett, C., and 11 others. <strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong> Nature Genet. 44: 972-974, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842231</a>] [<a href="https://doi.org/10.1038/ng.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842231">Chiang et al. (2012)</a>, see <a href="#0003">608700.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842231" 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">rs387907294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907294;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=rs387907294" 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=rs387907294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 sibs and 2 cousins from a consanguineous Pakistani pedigree with Leber congenital amaurosis (LCA9; <a href="/entry/608553">608553</a>), <a href="#8" class="mim-tip-reference" title="Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others. <strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong> Nature Genet. 44: 1040-1045, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842227">Falk et al. (2012)</a> identified homozygosity for a 25G-A transition in exon 2 of the NMNAT1 gene, resulting in a val9-to-met (V9M) substitution at a highly conserved residue. The mutation segregated with disease in the pedigree and was not found in 501 controls or in any public databases. Only 1 of the affected individuals had isolated LCA; 3 of the other LCA patients also had congenital deafness, and in those patients as well as in 2 other family members with congenital deafness, homozygosity for a nonsense mutation in the GJB2 gene (W24X; <a href="/entry/121011#0003">121011.0003</a>) known to cause deafness (see DFNB1A, <a href="/entry/220290">220290</a>) was identified. Additional features in 4 of the LCA patients included global developmental delay and autism; <a href="#8" class="mim-tip-reference" title="Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others. <strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong> Nature Genet. 44: 1040-1045, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842227">Falk et al. (2012)</a> stated that those presentations likely had a separate genetic etiology from that of LCA and deafness in this pedigree. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842227" 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>.0010 SPONDYLOEPIPHYSEAL DYSPLASIA, SENSORINEURAL HEARING LOSS, IMPAIRED INTELLECTUAL DEVELOPMENT, AND LEBER CONGENITAL AMAUROSIS</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001358652 OR RCV001358653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001358652, RCV001358653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001358652...</a>
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<p><strong><em>Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis</em></strong></p><p>
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In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy (P3; 947-13) with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; <a href="/entry/619260">619260</a>), <a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> identified homozygosity for a 7.4-kb duplication (c.299+526_Ter968dup, NM_022787.3) involving exons 4 and 5 of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The unaffected parents were heterozygous for the duplication, which was found to be embedded in a common haplotype, indicating that it represented a founder mutation. The authors suggested that the Alu elements flanking the duplicated fragment, AluSx and AluSx3, might have mediated a tandem duplication event by nonallelic homologous recombination. Analysis of patient fibroblasts showed a 4-fold downregulation of NMNAT1, and RT-PCR revealed a heterogeneous population of aberrant mRNA isoforms, variably showing partial retention of intron 3, duplication of exon 4, and duplication of exon 4 and part of exon 5, as well as some wildtype transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2-year-old Spanish girl with SHILCA syndrome, <a href="#1" class="mim-tip-reference" title="Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. <strong>New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform.</strong> Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33668384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33668384</a>] [<a href="https://doi.org/10.3390/ijms22052262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33668384">Abad-Morales et al. (2021)</a> identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation (c.439+5G-T) in intron 4 of the NMNAT1 gene. Her unaffected father, who was of Bulgarian origin, was heterozygous for the splicing mutation; DNA was unavailable from her biological mother, as the child was born from an ovum donation procedure. Total NMNAT1 expression in the proband was reduced by approximately 25% compared to controls. Expression assays indicated that the duplication decreases the levels of the known NMNAT1 canonical isoform 1 and alternative isoform 2, whereas the splicing mutation alters the relative expression of NMNAT1 isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33668384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Leber Congenital Amaurosis 9</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C. <strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong> Hum. Molec. Genet. 29: 2250-2260, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32533184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32533184</a>] [<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32533184">Bedoni et al. (2020)</a> performed PCR screening in a Spanish cohort of 76 patients with Leber congenital amaurosis (LCA) or early-onset retinal dystrophy and identified a 6-year-old boy with LCA (LCA9; <a href="/entry/608553">608553</a>) who was compound heterozygous for the common E257K variant in the NMNAT1 gene (<a href="#0002">608700.0002</a>) and the 7.4-bp duplication. Haplotype analysis in the Spanish boy revealed rare heterozygous SNP genotypes in proximity to the duplication which were shared with the Italian patients, indicating a common and likely remote ancestral genetic event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32533184" 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">rs1641939445 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1641939445;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=rs1641939445" 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=rs1641939445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splicing mutation (c.439+5G-T, NM_022787.3) in intron 4 of the NMNAT1 gene that was found in compound heterozygous state in a 2-year-old Spanish girl with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; <a href="/entry/619260">619260</a>) by <a href="#1" class="mim-tip-reference" title="Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E. <strong>New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform.</strong> Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33668384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33668384</a>] [<a href="https://doi.org/10.3390/ijms22052262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33668384">Abad-Morales et al. (2021)</a>, see <a href="#0010">608700.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33668384" 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">rs1405020783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1405020783;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=rs1405020783" 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=rs1405020783" 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=RCV001372427 OR RCV001780269" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001372427, RCV001780269" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001372427...</a>
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<p>In a sister and brother from a consanguineous Arab family who had retinal degeneration within the first few years of life, accompanied by nummular macular atrophy (LCA9; <a href="/entry/608700">608700</a>), <a href="#11" class="mim-tip-reference" title="Khan, A. O., Budde, B. S., Nurnberg, P., Kawalia, A., Lenzner, S., Bolz, H. J. <strong>Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.</strong> Clin. Genet. 93: 149-154, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369829</a>] [<a href="https://doi.org/10.1111/cge.13022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28369829">Khan et al. (2018)</a> identified homozygosity for a c.500A-G transition in the NMNAT1 gene, resulting in an asn167-to-ser (N167S) substitution at a highly conserved residue within the NMNAT domain. The mutation segregated with disease in the family and was not found in the ExAC or gnomAD databases. Patient samples were not available for functional analysis of the mutation. Electroretinography, performed in the sister, showed reduced responses more of cones than rods, consistent with a cone-rod dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28369829" 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> rs1271498710 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1271498710;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/rs1271498710?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=rs1271498710" 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=rs1271498710" 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=RCV000664187 OR RCV001372429" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000664187, RCV001372429" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000664187...</a>
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<p>In a 26-year-old Indian woman (case 1) with early-onset retinal dystrophy and coloboma-like macular atrophy (LCA9; <a href="/entry/608700">608700</a>), <a href="#15" class="mim-tip-reference" title="Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V. <strong>NMNAT1 variants cause cone and cone-rod dystrophy.</strong> Europ. J. Hum. Genet. 26: 428-433, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29184169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29184169</a>] [<a href="https://doi.org/10.1038/s41431-017-0029-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29184169">Nash et al. (2018)</a> identified homozygosity for a c.271G-A transition (c.271G-A, NM_022787.3) in the NMNAT1 gene, resulting in a glu91-to-lys (E91K) substitution at a conserved residue. The variant was present in 1 of 245,660 alleles in the gnomAD database (minor allele frequency, 0.000004). The authors considered the loss of central vision and ERG findings in this patient to be consistent with cone dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29184169" 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 LEBER CONGENITAL AMAUROSIS 9</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> rs748902766 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748902766;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/rs748902766?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=rs748902766" 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=rs748902766" 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=RCV000171148 OR RCV001075815 OR RCV001256641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000171148, RCV001075815, RCV001256641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000171148...</a>
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<p>For discussion of the c.53A-G transition in the NMNAT1 gene, resulting in an asn18-to-ser (N18S) substitution, that was found in compound heterozygous state in patients with early-onset retinal dystrophy and severe macular atrophy (LCA9; <a href="/entry/608553">608553</a>) by <a href="#15" class="mim-tip-reference" title="Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V. <strong>NMNAT1 variants cause cone and cone-rod dystrophy.</strong> Europ. J. Hum. Genet. 26: 428-433, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29184169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29184169</a>] [<a href="https://doi.org/10.1038/s41431-017-0029-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29184169">Nash et al. (2018)</a> and <a href="#13" class="mim-tip-reference" title="Kumaran, N., Robson, A. G., Michaelides, M. <strong>A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum.</strong> Retin. Cases Brief Rep. 15: 139-144, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30004997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30004997</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30004997">Kumaran et al. (2021)</a>, see <a href="#0002">608700.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30004997+29184169" 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> rs986437232 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs986437232;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/rs986437232?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=rs986437232" 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=rs986437232" 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=RCV001372430 OR RCV003339625" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001372430, RCV003339625" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001372430...</a>
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<p>For discussion of the c.245T-C transition in the NMNAT1 gene, resulting in a val82-to-ala (V83A) substitution, that was found in compound heterozygous state in an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia (LCA9; <a href="/entry/608553">608553</a>) by <a href="#4" class="mim-tip-reference" title="Bedoukian, E. C., Zhu, X., Serrano, L. E., Scoles, D., Aleman, T. S. <strong>NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment.</strong> Retin. Cases Brief Rep. 4Mar, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32150116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32150116</a>] [<a href="https://doi.org/10.1097/ICB.0000000000000992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32150116">Bedoukian et al. (2020)</a>, see <a href="#0002">608700.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32150116" 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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Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33668384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33668384</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33668384" 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/10.3390/ijms22052262" target="_blank">Full Text</a>]
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Araki, T., Sasaki, Y., Milbrandt, J.
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<strong>Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.</strong>
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Science 305: 1010-1013, 2004.
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[<a href="https://doi.org/10.1126/science.1098014" target="_blank">Full Text</a>]
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<strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddaa112" target="_blank">Full Text</a>]
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<strong>NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment.</strong>
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[<a href="https://doi.org/10.1097/ICB.0000000000000992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M508660200" target="_blank">Full Text</a>]
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<strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong>
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Nature Genet. 44: 972-974, 2012.
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[<a href="https://doi.org/10.1038/ng.2370" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M008700200" target="_blank">Full Text</a>]
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<strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong>
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Nature Genet. 44: 1040-1045, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842227[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=22842227" 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/ng.2361" target="_blank">Full Text</a>]
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<strong>Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse.</strong>
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[<a href="https://doi.org/10.1016/s0378-1119(02)00394-3" target="_blank">Full Text</a>]
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<strong>Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5200981" target="_blank">Full Text</a>]
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<strong>Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.</strong>
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Clin. Genet. 93: 149-154, 2018.
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[<a href="https://doi.org/10.1111/cge.13022" target="_blank">Full Text</a>]
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<strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong>
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Nature Genet. 44: 1035-1039, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842230</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842230[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=22842230" 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/ng.2356" target="_blank">Full Text</a>]
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<strong>A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum.</strong>
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[<a href="https://doi.org/10.1097/ICB.0000000000000754" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.04.028" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41431-017-0029-7" target="_blank">Full Text</a>]
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<strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong>
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[<a href="https://doi.org/10.1038/ng.2357" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7554/eLife.62027" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248244" 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/s0014-5793(01)02180-9" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Williams2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williams, P. A., Harder, J. M., Foxworth, N. E., Cichran, K. E., Philip, V. M., Porciatti, V., Smithies, O., John, S. W. M.
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<strong>Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.</strong>
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Science 355: 756-760, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28209901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28209901</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28209901" 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.aal0092" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Zhai2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., Bellen, H. J.
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<strong>Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.</strong>
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PLoS Biol. 4: e416, 2006. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17132048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17132048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17132048[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=17132048" 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/10.1371/journal.pbio.0040416" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Zhai2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., Bellen, H. J.
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<strong>NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.</strong>
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Nature 452: 887-891, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18344983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18344983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18344983[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=18344983" 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/nature06721" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Zhang2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., Zhang, H.
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<strong>Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis.</strong>
|
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J. Biol. Chem. 278: 13503-13511, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12574164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12574164</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12574164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M300073200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Zhou2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, T., Kurnasov, O., Tomchick, D. R., Binns, D. D., Grishin, N. V., Marquez, V. E., Osterman, A. L., Zhang, H.
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<strong>Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase: basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.</strong>
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J. Biol. Chem. 277: 13148-13154, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788603</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M111469200" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 04/09/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 04/07/2021<br>Marla J. F. O'Neill - updated : 04/06/2021<br>Ada Hamosh - updated : 08/14/2017<br>Patricia A. Hartz - updated : 10/23/2012<br>Marla J. F. O'Neill - updated : 9/19/2012<br>Ada Hamosh - updated : 8/12/2008<br>Ada Hamosh - updated : 11/30/2004
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 5/28/2004
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/09/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 04/07/2021<br>mgross : 04/07/2021<br>alopez : 04/06/2021<br>carol : 08/15/2017<br>alopez : 08/14/2017<br>mcolton : 03/30/2015<br>carol : 4/22/2013<br>mgross : 11/7/2012<br>terry : 10/23/2012<br>carol : 9/19/2012<br>terry : 9/19/2012<br>alopez : 8/26/2008<br>terry : 8/15/2008<br>terry : 8/12/2008<br>tkritzer : 12/1/2004<br>terry : 11/30/2004<br>mgross : 5/28/2004
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608700
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</span>
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<div>
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<h3>
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<span class="mim-font">
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NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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NMNAT<br />
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PYRIDINE NUCLEOTIDE ADENYLYLTRANSFERASE 1; PNAT1
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</span>
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<div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NMNAT1</em></strong>
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<strong>
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<em>
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Cytogenetic location: 1p36.22
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:9,942,923-9,996,892 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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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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Inheritance
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<th>
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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1p36.22
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<td>
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<span class="mim-font">
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Leber congenital amaurosis 9
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<span class="mim-font">
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608553
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis
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619260
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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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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca(2+) signaling pathways. NMNAT (EC 2.7.7.1) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD (Zhang et al., 2003). </p>
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<div>
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<br />
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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 class="mim-text-font">
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<p>By searching an EST database for sequences similar to peptide fragments of NMNAT1 purified from placenta, followed by PCR of a placenta cDNA library, Emanuelli et al. (2001) cloned NMNAT1. The deduced 279-amino acid protein has a calculated molecular mass of 31.9 kD. It contains a conserved N-terminal adenylyltransferase motif, an N-terminal N-glycosylation site, and several potential transmembrane regions. Northern blot analysis detected 3.1- and 4.1-kb transcripts expressed at variable levels in all tissues examined. The 3.1-kb transcript was more abundant, and expression was highest in skeletal muscle, heart, liver, and kidney; thymus and spleen showed a weak signal. Expression was reduced in all tumor cell lines examined except in a lymphoma cell line and a chronic myelogenous leukemia cell line. Purified recombinant NMNAT1 migrated with an apparent molecular mass of 33 kD by SDS-PAGE. Gel filtration analysis detected active recombinant enzyme at an apparent molecular mass of 139 kD, suggesting that NMNAT1 forms a homotetramer. </p><p>Schweiger et al. (2001) cloned NMNAT1 from a lymphoblastoid cell cDNA library. The deduced protein contains an N-terminal nuclear localization signal. Immunofluorescence microscopy localized endogenous NMNAT1 to the nucleus in human fibroblasts and in a hepatoma cell line. </p><p>Fernando et al. (2002) determined that the human and mouse NMNAT1 proteins share 78.4% amino acid identity. Northern blot analysis detected an abundant 3.1-kb transcript and a less abundant 4.1-kb transcript in skeletal muscle, heart, and all brain regions examined. </p><p>Using immunofluorescence analysis, Berger et al. (2005) showed that fluorescence-tagged NMNAT1 localized exclusively within nuclei of transfected HeLa and HEK293 cells, similar to the endogenous protein. </p><p>In addition to canonical isoform 1 of NMNAT1 and alternative isoform 2, Bedoni et al. (2020) identified a third isoform present in healthy human tissues. Levels of expression were highest for isoform 1 in all tissues tested, followed by isoform 2; novel isoform 3 presented lower levels of expression, but was always detected. </p><p>Using an Nmnat1-lacZ fusion protein lacking the nuclear localization signal, Sasaki et al. (2020) showed that Nmnat1 was ubiquitously expressed in mouse retina. </p>
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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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<span class="mim-text-font">
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<p>Fernando et al. (2002) determined that the NMNAT1 gene contains 4 exons. </p>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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 FISH, Emanuelli et al. (2001) mapped the NMNAT1 gene to chromosome 1p35-p32. Southern blot analysis indicated that NMNAT1 is a single-copy gene. </p><p>Using FISH, Fernando et al. (2002) mapped the NMNAT1 gene to chromosome 1p36.2 in a region that shows homology of synteny to distal mouse chromosome 4. FISH and genomic sequence analyses identified several NMNAT1 homologs on chromosomes 3, 4, 14, and 15. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zhou et al. (2002) solved the crystal structures of NMNAT1 in complex with NAD, deamido-NAD, and a nonhydrolyzable analog of the anticancer drug tiazofurin. The structures suggested a mechanism for the broad substrate specificity of the enzyme toward both NMN and NaMN and for adenylation of tiazofurin nucleotide. The crystal structure also showed that NMNAT1 forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role in interacting with nuclear transporting proteins. Analytic ultracentrifugation results were consistent with the formation of a hexamer in solution under certain conditions. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Emanuelli et al. (2001) confirmed that recombinant NMNAT1 exhibited adenylyltransferase activity, converting NMN to NAD in the presence of ATP. When deamido-NMN was used as the substrate, the rate of reaction was comparable to that for NMN, but the K(m) was higher, suggesting that the amido pathway is predominant. NMNAT1 had an absolute requirement for divalent cations, with optimum activity with 12 mM Mg(2+), and activity was depressed by several heavy metal ions. NMNAT1 also showed a broad pH optimum, ranging from pH 6.0 to 8.0, similar to NMNAT purified from other species. </p><p>Schweiger et al. (2001) demonstrated that NMNAT1 inhibited recombinant human poly(ADP-ribose) polymerase-1 (ADPRT; 173870) by about 35%, and it completely prevented the formation of branched ADP-ribose polymers. NMNAT1 was not itself an acceptor protein for ADP-ribosylation. Incubation with nuclear extracts resulted in phosphorylation of recombinant NMNAT1. </p><p>In Wallerian degeneration slow (wld-s) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wld-s) composed of the ubiquitin assembly protein Ufd2a (603753) and Nmnat1. Araki et al. (2004) demonstrated that increased Nmnat activity is responsible for the axon-sparing activity of the Wld-s protein. Furthermore, they demonstrated that Sirt1 (604479) is the downstream effector of increased Nmnat activity that leads to axonal protection. Araki et al. (2004) concluded that novel therapeutic strategies directed at increasing the supply of NAD and/or SIR2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration. </p><p>Using purified recombinant proteins, Berger et al. (2005) compared the enzymatic properties of NMNAT1, NMNAT2 (608701), and NMNAT3 (608702). NMNAT3 exhibited a high tolerance for substrate modifications. In contrast with the preferred NAD+ synthesis by NMNAT1, NMNAT2 and NMNAT3 could also form NADH directly from the reduced nicotinamide mononucleotide. A variety of physiologic intermediates had only minor influence on NMNAT catalytic activity. However, gallotannin was a potent inhibitor of NMNAT catalytic activity. </p><p>Studies in Drosophila (see ANIMAL MODEL) have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase against activity-induced neurodegeneration and injury-induced axonal degeneration (Zhai et al., 2006, MacDonald et al., 2006). Zhai et al. (2008) showed that NMNAT overexpression can also protect against ataxin (601556)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein-70 (HSP70; 140550). NMNAT displayed chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of polyglutamine-expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Zhai et al. (2008) concluded that their results implicated NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Leber Congenital Amaurosis 9</em></strong></p><p>
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In 8 families with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified homozygosity or compound heterozygosity for missense mutations in the NMNAT1 gene (see, e.g., 608700.0001-608700.0007) that segregated with disease in each family. </p><p>In 11 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for missense and/or nonsense mutations in the NMNAT1 gene (see, e.g., 608700.0002-608700.0004 and 608700.0006). The most common variant, E257K (rs150726175; 608700.0002), was present as 1 of 2 variant alleles in all 11 probands and was estimated to have an allele frequency of 0.001. </p><p>In affected individuals from 14 families with severe LCA, Falk et al. (2012) identified homozygosity or compound heterozygosity for missense and/or frameshift mutations in the NMNAT1 gene (see, e.g., 608700.0009), including 6 patients who carried the E257K mutation on 1 allele. </p><p>In 22 of 261 LCA probands without mutations in known LCA genes, Perrault et al. (2012) identified homozygosity (608700.0006) or compound heterozygosity for mutations in the NMNAT1 gene (see, e.g., 608700.0002 and 608700.0005). In 7 probands, only a single heterozygous NMNAT1 mutation was found, but because they presented an identical phenotype to that of patients in whom 2 mutations were identified it was likely that they harbored a second undetected NMNAT1 mutant allele. The most common mutation detected was the E257K variant, which was present on 1 allele in 23 of the 29 index cases with mutation in NMNAT1. </p><p>In an Arab sister and brother with early-onset retinal dystrophy with central nummular macular atrophy, Khan et al. (2018) identified homozygosity for a missense mutation in the NMNAT1 gene (N167S; 608700.0012) that segregated with disease in the family and was not found in public variant databases. </p><p>In a 26-year-old Indian woman with early-onset retinal dystrophy and coloboma-like macular atrophy, Nash et al. (2018) identified homozygosity for a missense mutation in the NMNAT1 gene (E91K; 608700.0013). A similarly affected 14-year-old Caucasian girl was found to be compound heterozygous for the common E257K variant and another missense mutation in the NMNAT1 gene (N18S; 608700.0014). </p><p>From a Spanish cohort of 76 patients with LCA or early-onset retinal dystrophy, Bedoni et al. (2020) identified a 6-year-old boy with LCA who was compound heterozygous for the common E257K variant and a 7.4-bp duplication within the NMNAT1 gene (608700.0010). </p><p>In an Egyptian brother and sister with early-onset progressive retinal dysfunction with foveal hypoplasia, Bedoukian et al. (2020) identified compound heterozygous mutations in the NMNAT1 gene: the E257K variant and another missense mutation (V82L; 608700.0015). The authors concluded that NMNAT1 mutations cause a consistent phenotype characterized by early-onset progressive retina-wide dysfunction, affecting cones more than rods, with predominantly central abnormalities ranging from hypoplasia to atrophy of the fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance. </p><p>In a sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene, noting that these cases extended the phenotypic spectrum associated with the NMNAT1 gene. </p><p><strong><em>Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis</em></strong></p><p>
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In an Italian brother and sister and an unrelated Italian boy with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication within the NMNAT1 gene (608700.0010). </p><p>In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation in the NMNAT1 gene (608700.0011). </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>Zhai et al. (2006) found that knockdown of Nmnat in Drosophila resulted in retinal neurodegeneration that was exacerbated by neural activity. Neurodegeneration was independent of apoptosis. Overexpression of an inactive Nmnat mutant protected mutant retinas from activity-induced neurodegeneration, suggesting a dual role for Nmnat in NAD synthesis and in maintaining neuronal integrity. </p><p>Studying glaucoma-prone mice (the DBA/2J strain), Williams et al. (2017) showed that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults, including increased intraocular pressure. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD(+)-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. Williams et al. (2017) concluded that their results supported therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations. </p><p>Sasaki et al. (2020) noted that knockout of Nmnat1 in mice is embryonic lethal. They found that conditional knockout of Nmnat1 in 2-month-old mice induced loss of photoreceptor cells and inhibited retinal function, leading to severe retinal degeneration. Photoreceptor-specific depletion of Nmnat1 also resulted in retinal degeneration, which could be partially rescued by transgenic expression of Nmnat1. Further analysis demonstrated that loss of Nmnat1 in photoreceptors activated Sarm1 (607732), and that Sarm1 was required for subsequent photoreceptor degeneration and loss of visual function. Consequently, depletion of Sarm1 rescued retinal degeneration in Nmnat1-deficient retina. </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 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, TER280GLN
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<br />
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SNP: rs387907290,
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ClinVar: RCV000030763
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large consanguineous Pakistani family with Leber congenital amaurosis (LCA9; 608553), originally reported by Keen et al. (2003), Koenekoop et al. (2012) identified homozygosity for an 838T-C transition in the NMNAT1 gene, resulting in a ter280-to-gln (X280Q) substitution that was predicted to elongate the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, GLU257LYS ({dbSNP rs150726175})
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<br />
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SNP: rs150726175,
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gnomAD: rs150726175,
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ClinVar: RCV000030765, RCV000255806, RCV000504859, RCV000664188, RCV001003567, RCV001075816, RCV004639123, RCV004757953
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 5 probands with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified a 769G-A transition in exon 5 of the NMNAT1 gene, resulting in a glu257-to-lys (E257K) substitution at a conserved residue in a protein-interaction domain interface, predicted to interfere with hexamer formation. The mutation was found in homozygosity in 1 proband, and was present in compound heterozygosity with another missense mutation in the NMNAT1 gene in the other 4 probands (see, e.g., 608700.0003-608700.0005). All mutations segregated with disease in each family and were not found in 200 controls. In red blood cells (RBCs) from the patient homozygous for E257K there was a significantly lower concentration of NAD compared with that in RBCs from his heterozygous mother, suggesting reduced enzymatic function of the mutant protein. Immunohistochemical studies in transfected HeLa cells demonstrated that whereas wildtype NMNAT1 showed strong nuclear staining, the E257K mutant stained strongly outside of the cell nucleus in the cytoplasm; in addition, the mutant protein was positive for ubiquitin staining, indicating that the mutation likely affects protein folding. In vitro assay showed significantly reduced enzymatic activity with the E257K mutant protein compared to wildtype. </p><p>In 11 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or nonsense mutation in the NMNAT1 gene (see, e.g., N273D, 608700.0003; V151F, 608700.0004; and W169X, 608700.0006). Chiang et al. (2012) stated that the allele frequency of E257K (rs150726175) was estimated to be 0.001, whereas the remainder of the variants had not been reported in any public database. </p><p>In 6 probands with LCA, Falk et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or frameshift mutation in the NMNAT1 gene. </p><p>Perrault et al. (2012) identified the E257K variant on 1 allele in 23 of 29 probands with LCA in whom mutation in NMNAT1 was detected. </p><p>In a 6-year-old Spanish boy with LCA, Bedoni et al. (2020) identified compound heterozygosity for the E257K variant and a 7.4-kb duplication within the NMNAT1 gene (608700.0010). </p><p>In a 14-year-old Caucasian girl (case 2) with early-onset retinal dystrophy and coloboma-like macular atrophy, Nash et al. (2018) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.53A-G transition, resulting in an asn18-to-ser (N18S; 608700.0014) substitution. The N18S variant was present in 5 of 276,912 alleles in the gnomAD database (minor allele frequency, 0.000018). The authors noted that ERG findings in this patient showed reduced photopic and scotopic responses, consistent with cone-rod dystrophy. </p><p>In an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia, consistent with cone-rod dystrophy, Bedoukian et al. (2020) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.245T-C transition, resulting in a val82-to-ala (V82A; 608700.0015) substitution. Their unaffected parents were each heterozygous for one of the mutations. </p><p>In a sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene. Their unaffected parents were each heterozygous for one of the mutations. </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>.0003 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, ASN273ASP
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<br />
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SNP: rs387907291,
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gnomAD: rs387907291,
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ClinVar: RCV000030766
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 56-year-old French Canadian woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for an 817A-G transition in exon 5 of the NMNAT1 gene, resulting in an asn273-to-asp (N273D) substitution at a conserved residue, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. </p><p>In an 8-year-old Canadian boy of western European ancestry who had severe LCA, Chiang et al. (2012) identified compound heterozygosity for the N273D and E257K mutations in the NMNAT1 gene. The E257K and N273D mutations were inherited from his unaffected mother and father, respectively, and a third mutation was detected on the paternal allele as well: a 457C-G transversion in the NMNAT1 gene, resulting in a leu153-to-val (L153V; 608700.0008) substitution near the site of ligand binding, predicted to disturb local interactions and affect enzymatic activity. At 7 years of age, ERG showed primarily cone dysfunction rather than profound loss of all responses, and the patient's diagnosis was revised from 'variant LCA' to 'cone-rod dystrophy.' </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>.0004 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, VAL151PHE
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<br />
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SNP: rs387907292,
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gnomAD: rs387907292,
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ClinVar: RCV000030767
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a European female with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 451G-A transition in exon 5 of the NMNAT1 gene, resulting in a val151-to-phe (V151F) substitution at a conserved residue in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. </p><p>In a 26-year-old Canadian man of Greek ancestry with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the V151F and E257K mutations in the NMNAT1 gene. At 6 months of age, the patient was diagnosed with retinitis pigmentosa (see 268000), but the diagnosis was later changed to LCA. Major vision loss occurred around 18 years of age, with colors and shapes still seen at age 20, at which time he began using a guide dog. Colors and shapes were lost at 22 years and 24 years of age, respectively, and by 26 years of age, the patient could only distinguish between light and dark. Eye examination showed wandering eye movements, macular atrophic lesions, attenuated vessels, and bone spicule pigmentation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, ARG207TRP
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<br />
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SNP: rs142968179,
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gnomAD: rs142968179,
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ClinVar: RCV000030764, RCV001090803, RCV004794346
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 13-year-old French Canadian boy with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 619C-T transition in exon 5 of the NMNAT1 gene, resulting in an arg207-to-trp (R207W) substitution in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype. </p><p>In 7 unrelated probands with LCA, Perrault et al. (2012) identified compound heterozygosity for the R207W and E257K mutations in the NMNAT1 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 LEBER CONGENITAL AMAUROSIS 9</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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NMNAT1, TRP169TER
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<br />
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SNP: rs371526758,
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|
|
|
gnomAD: rs371526758,
|
|
|
|
|
|
ClinVar: RCV000030768, RCV000255071, RCV004649113, RCV004757984
|
|
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 33-year-old Irish woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 507G-A transition in exon 5 of the NMNAT1 gene, resulting in a trp169-to-ter (W169X) substitution, and a 710G-T transversion in exon 5, resulting in an arg237-to-leu (R237L; 608700.0007) substitution, both at conserved residues in the adenylyltransferase domain. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 200 controls. </p><p>In 4 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the W169X and E257K (608700.0002) mutations in the NMNAT1 gene. Chiang et al. (2012) noted that these patients who carried the nonsense mutation W169X in combination with E257K were all blind at birth and had only varying degrees of light perception still present, whereas 5 patients who carried various missense mutations in combination with E257K had vision that decreased within a few years after birth. </p><p>In a 16-year-old girl with LCA who was born of consanguineous Algerian parents, Perrault et al. (2012) identified homozygosity for the W169X mutation in the NMNAT1 gene. Her unaffected parents and sister were heterozygous for the mutation, which was not found in 200 controls. The patient had high hyperopia, night blindness, visual acuity at the level of counting fingers since 4 years of age, and macular alteration. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
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<span class="mim-font">
|
|
<strong>.0007 LEBER CONGENITAL AMAUROSIS 9</strong>
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|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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NMNAT1, ARG237LEU
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<br />
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SNP: rs368062092,
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gnomAD: rs368062092,
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ClinVar: RCV000030769
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the arg273-to-leu (R273L) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; 608553) by Koenekoop et al. (2012), see 608700.0006. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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NMNAT1, LEU153VAL
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<br />
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SNP: rs387907293,
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gnomAD: rs387907293,
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|
|
ClinVar: RCV000030770
|
|
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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>For discussion of the leu153-to-val (L153V) mutation in the NMNAT1 gene that was found in compound heterozygous state in a patient with severe Leber congenital amaurosis (LCA9; 608553) by Chiang et al. (2012), see 608700.0003. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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NMNAT1, VAL9MET
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<br />
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SNP: rs387907294,
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|
|
ClinVar: RCV000030771, RCV004794347
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|
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|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 3 sibs and 2 cousins from a consanguineous Pakistani pedigree with Leber congenital amaurosis (LCA9; 608553), Falk et al. (2012) identified homozygosity for a 25G-A transition in exon 2 of the NMNAT1 gene, resulting in a val9-to-met (V9M) substitution at a highly conserved residue. The mutation segregated with disease in the pedigree and was not found in 501 controls or in any public databases. Only 1 of the affected individuals had isolated LCA; 3 of the other LCA patients also had congenital deafness, and in those patients as well as in 2 other family members with congenital deafness, homozygosity for a nonsense mutation in the GJB2 gene (W24X; 121011.0003) known to cause deafness (see DFNB1A, 220290) was identified. Additional features in 4 of the LCA patients included global developmental delay and autism; Falk et al. (2012) stated that those presentations likely had a separate genetic etiology from that of LCA and deafness in this pedigree. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPONDYLOEPIPHYSEAL DYSPLASIA, SENSORINEURAL HEARING LOSS, IMPAIRED INTELLECTUAL DEVELOPMENT, AND LEBER CONGENITAL AMAUROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
LEBER CONGENITAL AMAUROSIS 9, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
NMNAT1, 7.4-KB DUP
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<br />
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|
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ClinVar: RCV001358652, RCV001358653
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Spondyloepiphyseal Dysplasia, Sensorineural Hearing Loss, Impaired Intellectual Development, and Leber Congenital Amaurosis</em></strong></p><p>
|
|
In an Italian brother (UD-NA011-P1) and sister (UD-NA011-P2) and an unrelated Italian boy (P3; 947-13) with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260), Bedoni et al. (2020) identified homozygosity for a 7.4-kb duplication (c.299+526_Ter968dup, NM_022787.3) involving exons 4 and 5 of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The unaffected parents were heterozygous for the duplication, which was found to be embedded in a common haplotype, indicating that it represented a founder mutation. The authors suggested that the Alu elements flanking the duplicated fragment, AluSx and AluSx3, might have mediated a tandem duplication event by nonallelic homologous recombination. Analysis of patient fibroblasts showed a 4-fold downregulation of NMNAT1, and RT-PCR revealed a heterogeneous population of aberrant mRNA isoforms, variably showing partial retention of intron 3, duplication of exon 4, and duplication of exon 4 and part of exon 5, as well as some wildtype transcript. </p><p>In a 2-year-old Spanish girl with SHILCA syndrome, Abad-Morales et al. (2021) identified compound heterozygosity for the 7.4-kb duplication and a splicing mutation (c.439+5G-T) in intron 4 of the NMNAT1 gene. Her unaffected father, who was of Bulgarian origin, was heterozygous for the splicing mutation; DNA was unavailable from her biological mother, as the child was born from an ovum donation procedure. Total NMNAT1 expression in the proband was reduced by approximately 25% compared to controls. Expression assays indicated that the duplication decreases the levels of the known NMNAT1 canonical isoform 1 and alternative isoform 2, whereas the splicing mutation alters the relative expression of NMNAT1 isoforms. </p><p><strong><em>Leber Congenital Amaurosis 9</em></strong></p><p>
|
|
Bedoni et al. (2020) performed PCR screening in a Spanish cohort of 76 patients with Leber congenital amaurosis (LCA) or early-onset retinal dystrophy and identified a 6-year-old boy with LCA (LCA9; 608553) who was compound heterozygous for the common E257K variant in the NMNAT1 gene (608700.0002) and the 7.4-bp duplication. Haplotype analysis in the Spanish boy revealed rare heterozygous SNP genotypes in proximity to the duplication which were shared with the Italian patients, indicating a common and likely remote ancestral genetic event. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPONDYLOEPIPHYSEAL DYSPLASIA, SENSORINEURAL HEARING LOSS, IMPAIRED INTELLECTUAL DEVELOPMENT, AND LEBER CONGENITAL AMAUROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NMNAT1, IVS4, G-T, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1641939445,
|
|
|
|
|
|
|
|
ClinVar: RCV001358654
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splicing mutation (c.439+5G-T, NM_022787.3) in intron 4 of the NMNAT1 gene that was found in compound heterozygous state in a 2-year-old Spanish girl with spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA; 619260) by Abad-Morales et al. (2021), see 608700.0010. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NMNAT1, ASN167SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1405020783,
|
|
|
|
|
|
|
|
ClinVar: RCV001372427, RCV001780269
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sister and brother from a consanguineous Arab family who had retinal degeneration within the first few years of life, accompanied by nummular macular atrophy (LCA9; 608700), Khan et al. (2018) identified homozygosity for a c.500A-G transition in the NMNAT1 gene, resulting in an asn167-to-ser (N167S) substitution at a highly conserved residue within the NMNAT domain. The mutation segregated with disease in the family and was not found in the ExAC or gnomAD databases. Patient samples were not available for functional analysis of the mutation. Electroretinography, performed in the sister, showed reduced responses more of cones than rods, consistent with a cone-rod dystrophy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NMNAT1, GLU91LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1271498710,
|
|
|
|
|
|
gnomAD: rs1271498710,
|
|
|
|
|
|
ClinVar: RCV000664187, RCV001372429
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old Indian woman (case 1) with early-onset retinal dystrophy and coloboma-like macular atrophy (LCA9; 608700), Nash et al. (2018) identified homozygosity for a c.271G-A transition (c.271G-A, NM_022787.3) in the NMNAT1 gene, resulting in a glu91-to-lys (E91K) substitution at a conserved residue. The variant was present in 1 of 245,660 alleles in the gnomAD database (minor allele frequency, 0.000004). The authors considered the loss of central vision and ERG findings in this patient to be consistent with cone dystrophy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NMNAT1, ASN18SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs748902766,
|
|
|
|
|
|
gnomAD: rs748902766,
|
|
|
|
|
|
ClinVar: RCV000171148, RCV001075815, RCV001256641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.53A-G transition in the NMNAT1 gene, resulting in an asn18-to-ser (N18S) substitution, that was found in compound heterozygous state in patients with early-onset retinal dystrophy and severe macular atrophy (LCA9; 608553) by Nash et al. (2018) and Kumaran et al. (2021), see 608700.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LEBER CONGENITAL AMAUROSIS 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NMNAT1, VAL82ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs986437232,
|
|
|
|
|
|
gnomAD: rs986437232,
|
|
|
|
|
|
ClinVar: RCV001372430, RCV003339625
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.245T-C transition in the NMNAT1 gene, resulting in a val82-to-ala (V83A) substitution, that was found in compound heterozygous state in an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia (LCA9; 608553) by Bedoukian et al. (2020), see 608700.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
|
|
|
</div>
|
|
|
|
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|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abad-Morales, V., Wert, A., Ruiz Gomez, M. A., Navarro, R., Pomares, E.
|
|
<strong>New insights on the genetic basis underlying SHILCA syndrome: characterization of the NMNAT1 pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform.</strong>
|
|
Int. J. Molec. Sci. 22: 2262, 2021. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 33668384]
|
|
|
|
|
|
[Full Text: https://doi.org/10.3390/ijms22052262]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Araki, T., Sasaki, Y., Milbrandt, J.
|
|
<strong>Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.</strong>
|
|
Science 305: 1010-1013, 2004.
|
|
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|
|
[PubMed: 15310905]
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[Full Text: https://doi.org/10.1126/science.1098014]
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</p>
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|
</li>
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<li>
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<p class="mim-text-font">
|
|
Bedoni, N., Quinodoz, M., Pinelli, M., Cappuccio, G., Torella, A., Nigro, V., Testa, F., Simonelli, F, TUDP (Telethon Undiagnosed Disease Program), Corton, M., Lualdi, S., Lanza, F., Morana, G., Ayuso, C., Di Rocco, M., Filocamo, M., Banfi, S., Brunetti-Pierri, N., Superti-Furga, A., Rivolta, C.
|
|
<strong>An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.</strong>
|
|
Hum. Molec. Genet. 29: 2250-2260, 2020.
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|
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|
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|
[PubMed: 32533184]
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[Full Text: https://doi.org/10.1093/hmg/ddaa112]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bedoukian, E. C., Zhu, X., Serrano, L. E., Scoles, D., Aleman, T. S.
|
|
<strong>NMNAT1-associated cone-rod dystrophy: evidence for a spectrum of foveal maldevelopment.</strong>
|
|
Retin. Cases Brief Rep. 4Mar, 2020.
|
|
|
|
|
|
[PubMed: 32150116]
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|
|
[Full Text: https://doi.org/10.1097/ICB.0000000000000992]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Berger, F., Lau, C., Dahlmann, M., Ziegler, M.
|
|
<strong>Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms.</strong>
|
|
J. Biol. Chem. 280: 36334-36341, 2005.
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|
[PubMed: 16118205]
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|
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<strong>Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.</strong>
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Falk, M. J., Zhang, Q., Nakamaru-Ogiso, E., Kannabiran, C., Fonseca-Kelly, Z., Chakarova, C., Audo, S., Mackay, D. S., Zeitz, C., Borman, A. D., Staniszewska, M., Shukla, R., and 17 others.
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<strong>NMNAT1 mutations cause Leber congenital amaurosis.</strong>
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Fernando, F. S., Conforti, L., Tosi, S., Smith, A. D., Coleman, M. P.
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<strong>Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(S)) mouse.</strong>
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Keen, T. J., Mohamed, M. D., McKibbin, M., Rashid, Y., Jafri, H., Maumenee, I. H., Inglehearn, C. F.
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<strong>Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36.</strong>
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Khan, A. O., Budde, B. S., Nurnberg, P., Kawalia, A., Lenzner, S., Bolz, H. J.
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<strong>Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.</strong>
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Koenekoop, R. K., Wang, H., Majewski, J., Wang, X., Lopez, I., Ren, H., Chen, Y., Li, Y., Fishman, G. A., Genead, M., Schwartzentruber, J., Solanki, N., and 21 others.
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<strong>Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.</strong>
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Nature Genet. 44: 1035-1039, 2012.
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[PubMed: 22842230]
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Kumaran, N., Robson, A. G., Michaelides, M.
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<strong>A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum.</strong>
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Retin. Cases Brief Rep. 15: 139-144, 2021.
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MacDonald, J. M., Beach, M. G., Porpiglia, E., Sheehan, A. E., Watts, R. J., Freeman, M. R.
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<strong>The Drosophila cell corpse engulfment receptor draper mediates glial clearance of severed axons.</strong>
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Nash, B. M., Symes, R., Goel, H., Dinger, M. E., Bennetts, B., Grigg, J. R., Jamieson R. V.
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<strong>NMNAT1 variants cause cone and cone-rod dystrophy.</strong>
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Europ. J. Hum. Genet. 26: 428-433, 2018.
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Perrault, I., Hanein, S., Zanlonghi, X., Serre, V., Nicouleau, M., Defoort-Delhemmes, S., Delphin, N., Fares-Taie, L., Gerber, S., Xerri, O., Edelson, C., Goldenberg, A., and 11 others.
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<strong>Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.</strong>
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Nature Genet. 44: 975-977, 2012.
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[PubMed: 22842229]
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[Full Text: https://doi.org/10.1038/ng.2357]
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Sasaki, Y., Kakita, H., Kubota, S., Sene, A., Lee, T. J., Ban, N., Dong, Z., Lin, J. B., Boye, S. L., DiAntonio, A., Boye, S. E., Apte, R. S., Milbrandt, J.
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<strong>SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.</strong>
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eLife 9: e62027, 2020.
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[PubMed: 33107823]
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Schweiger, M., Hennig, K., Lerner, F., Niere, M., Hirsch-Kauffmann, M., Specht, T., Weise, C., Oei, S. L., Ziegler, M.
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<strong>Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis.</strong>
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Williams, P. A., Harder, J. M., Foxworth, N. E., Cichran, K. E., Philip, V. M., Porciatti, V., Smithies, O., John, S. W. M.
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<strong>Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.</strong>
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Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., Bellen, H. J.
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<strong>Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.</strong>
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PLoS Biol. 4: e416, 2006. Note: Electronic Article.
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[PubMed: 17132048]
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Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., Bellen, H. J.
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<strong>NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.</strong>
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Nature 452: 887-891, 2008.
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Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., Zhang, H.
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<strong>Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis.</strong>
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Zhou, T., Kurnasov, O., Tomchick, D. R., Binns, D. D., Grishin, N. V., Marquez, V. E., Osterman, A. L., Zhang, H.
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<strong>Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase: basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.</strong>
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