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Entry
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- *600225 - GTP CYCLOHYDROLASE I; GCH1
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- OMIM
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<div class="container hidden-print">
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<div class="row">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600225</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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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>
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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>
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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="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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>
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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/600225">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=ENSG00000131979;t=ENST00000491895" 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=2643" 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=600225" 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=ENSG00000131979;t=ENST00000491895" 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_000161,NM_001024024,NM_001024070,NM_001024071,NM_001424104,NM_001424105,XM_047431261" 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_000161" 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=600225" 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=02573&isoform_id=02573_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/GCH1" 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/31954,255061,255063,255065,399536,563370,567017,755462,1006777,4503949,5058993,5058997,7242657,7242659,14009665,19343964,23345032,23345034,23345036,49168586,66932968,66932970,66932972,119601053,119601054,119601055,119601056,119601057,119601058,119601059,2217297132,2462539809,2572895178,2572895190" 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/P30793" 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=2643" 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=ENSG00000131979;t=ENST00000491895" 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=GCH1" 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=GCH1" 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+2643" 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/GCH1" 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:2643" 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/2643" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr14&hgg_gene=ENST00000491895.7&hgg_start=54842017&hgg_end=54902826&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/gene-dosage/HGNC:4193" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4193" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/gch1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600225[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=600225[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://www.deciphergenomics.org/gene/GCH1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000131979" 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=GCH1" 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=GCH1" 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=GCH1" 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="http://www.bh4.org/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GCH1&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/PA28608" 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:4193" 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/FBgn0003162.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:95675" 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/GCH1#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:95675" 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/2643/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=2643" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000298;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-001205-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2643" 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=GCH1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230332007, 23447005, 715768000<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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600225
|
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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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GTP CYCLOHYDROLASE I; GCH1
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GCH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GCH1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/14/252?start=-3&limit=10&highlight=252">14q22.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:54842017-54902826&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">14:54,842,017-54,902,826</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=128230,233910" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/252?start=-3&limit=10&highlight=252">
|
|
14q22.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Dystonia, DOPA-responsive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/128230"> 128230 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Hyperphenylalaninemia, BH4-deficient, B
|
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|
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</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
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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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<strong>TEXT</strong>
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<p>GTP cyclohydrolase I (<a href="https://enzyme.expasy.org/EC/3.5.4.16" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.5.4.16</a>) catalyzes the conversion of GTP to D-erythro-7,8-dihydroneopterin triphosphate, the first and rate-limiting step in tetrahydrobiopterin (BH4) biosynthesis. Tetrahydrobiopterin is an essential cofactor for 3 aromatic amino acid monooxygenases: phenylalanine, tyrosine, and tryptophan hydroxylases. Animals can synthesize tetrahydrobiopterin in vivo from GTP through several enzymatic reactions.</p>
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<p>By screening a human liver cDNA library, <a href="#31" class="mim-tip-reference" title="Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., Nagatsu, T. <strong>Multiple mRNA forms of human GTP cyclohydrolase I.</strong> Biochem. Biophys. Res. Commun. 187: 359-365, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1520321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1520321</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)81501-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1520321">Togari et al. (1992)</a> isolated 3 cDNAs corresponding to the GCH1 gene. All 3 cDNAs were identical in their central and 5-prime regions, but diverged at their 3-prime regions. <a href="#31" class="mim-tip-reference" title="Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., Nagatsu, T. <strong>Multiple mRNA forms of human GTP cyclohydrolase I.</strong> Biochem. Biophys. Res. Commun. 187: 359-365, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1520321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1520321</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)81501-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1520321">Togari et al. (1992)</a> concluded that, in humans, there are at least 3 distinct GCH1 mRNAs. <a href="#8" class="mim-tip-reference" title="Gutlich, M., Jaeger, E., Rucknagel, K. P., Werner, T., Rodl, W., Ziegler, I., Bacher, A. <strong>Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme.</strong> Biochem. J. 302: 215-221, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8068008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8068008</a>] [<a href="https://doi.org/10.1042/bj3020215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8068008">Gutlich et al. (1994)</a> determined that only the longest of the 3 cDNAs encodes an active enzyme of 250 amino acids. Proteins corresponding to the other 2 shorter cDNAs did not have enzymatic activity. By Northern blot analysis, <a href="#8" class="mim-tip-reference" title="Gutlich, M., Jaeger, E., Rucknagel, K. P., Werner, T., Rodl, W., Ziegler, I., Bacher, A. <strong>Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme.</strong> Biochem. J. 302: 215-221, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8068008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8068008</a>] [<a href="https://doi.org/10.1042/bj3020215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8068008">Gutlich et al. (1994)</a> detected a 3.6-kb mRNA in human tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1520321+8068008" 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="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> cloned both the human and mouse genes for GCH1, and determined that alternative use of the splice acceptor site in exon 6 is responsible for the observed heterogeneity of GCH1 mRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7730309" 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="#33" class="mim-tip-reference" title="Witter, K., Werner, T., Blusch, J. H., Schneider, E.-M., Riess, O., Ziegler, I., Rodl, W., Bacher, A., Gutlich, M. <strong>Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I.</strong> Gene 171: 285-290, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666288</a>] [<a href="https://doi.org/10.1016/0378-1119(95)00886-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666288">Witter et al. (1996)</a> identified a genomic clone containing the 5-prime regulatory region of the GCH1 gene. The transcription start point was mapped by 5-prime RACE. The 2.6-kb region upstream from the transcription start point showed promoter activity when ligated upstream from a reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8666288" 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="#16" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> determined that both the mouse and human GCH1 genes contain 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7730309" 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="#1" class="mim-tip-reference" title="Bandmann, O., Nygaard, T. G., Surtees, R., Marsden, C. D., Wood, N. W., Harding, A. E. <strong>Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity.</strong> Hum. Molec. Genet. 5: 403-406, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852666</a>] [<a href="https://doi.org/10.1093/hmg/5.3.403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8852666">Bandmann et al. (1996)</a> characterized the exon-intron boundaries of the GCH1 gene (which they symbolized GTPCH). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8852666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using somatic cell hybrids, <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> assigned the human GCH1 gene to chromosome 14. They regionalized the gene to 14q22.1-q22.2 by fluorescence in situ hybridization. <a href="#30" class="mim-tip-reference" title="Thony, B., Heizmann, C. W., Mattei, M.-G. <strong>Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization.</strong> Genomics 26: 168-170, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7782081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7782081</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80101-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7782081">Thony et al. (1995)</a> also mapped GCH1 to 14q21-q22 by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7782081+7874165" 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="#13" class="mim-tip-reference" title="Hwu, W.-L., Lu, M.-Y., Hwa, K.-Y., Fan, S.-W., Lee, Y.-M. <strong>Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia.</strong> Ann. Neurol. 55: 875-878, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174023</a>] [<a href="https://doi.org/10.1002/ana.20122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15174023">Hwu et al. (2004)</a> found that a subset of HeLa cells expressing the GCH gly201-to-glu mutation (G201E; <a href="#0004">600225.0004</a>) retained expression of the GCH protein, suggesting that they were resistant to the dominant-negative effect. Differential display showed that the resistant cells had a higher expression of the molecular chaperone Hsc70 (<a href="/entry/600816">600816</a>). Cotransfection of Hsp40 (<a href="/entry/604572">604572</a>) and Hsp70 (see <a href="/entry/140550">140550</a>) with G201E-containing HeLa cells resulted in higher expression of the mutant GCH protein compared to mutant cells without Hsp40 and Hsp70, although the protein had no activity. Expression of the chaperone protein Hsp90 (see <a href="/entry/140571">140571</a>) in both wildtype and mutant cells stabilized the GCH protein and increased protein synthesis without increasing GCH mRNA. <a href="#13" class="mim-tip-reference" title="Hwu, W.-L., Lu, M.-Y., Hwa, K.-Y., Fan, S.-W., Lee, Y.-M. <strong>Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia.</strong> Ann. Neurol. 55: 875-878, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174023</a>] [<a href="https://doi.org/10.1002/ana.20122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15174023">Hwu et al. (2004)</a> concluded that molecular chaperones regulate GCH at the protein level, that Hsp90 may assist GCH conformation and stability, and that these molecular chaperones may be modifier genes that underlie the variable phenotypic expression in dopa-responsive dystonia (<a href="/entry/128230">128230</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15174023" 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="#5" class="mim-tip-reference" title="Cronin, S. J. F., Seehus, C., Weidinger, A., Talbot, S., Reissig, S., Seifert, M., Pierson, Y., McNeill, E., Longhi, M. S., Turnes, B. L., Kreslavsky, T., Kogler, M., and 29 others. <strong>The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.</strong> Nature 563: 564-568, 2018. Note: Erratum: Nature 572: E18, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30405245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30405245</a>] [<a href="https://doi.org/10.1038/s41586-018-0701-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30405245">Cronin et al. (2018)</a> found that genetic inactivation of GCH1 and inhibition of sepiapterin reductase (SPR; <a href="/entry/182125">182125</a>), the terminal enzyme in the tetrahydrobiopterin (BH4) synthesis pathway, severely impaired the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogated T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augmented responses by CD4- and CD8-expressing T cells, increasing their antitumor activity in vivo. Administration of BH4 to mice markedly reduced tumor growth and expanded the population of intratumoral effector T cells. Kynurenine, a tryptophan metabolite that blocks antitumor immunity, inhibited T cell proliferation in a manner that could be rescued by BH4. Finally, <a href="#5" class="mim-tip-reference" title="Cronin, S. J. F., Seehus, C., Weidinger, A., Talbot, S., Reissig, S., Seifert, M., Pierson, Y., McNeill, E., Longhi, M. S., Turnes, B. L., Kreslavsky, T., Kogler, M., and 29 others. <strong>The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.</strong> Nature 563: 564-568, 2018. Note: Erratum: Nature 572: E18, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30405245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30405245</a>] [<a href="https://doi.org/10.1038/s41586-018-0701-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30405245">Cronin et al. (2018)</a> reported the development of a potent SPR antagonist for possible clinical use. Their data uncovered GCH1, SPR, and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30405245" 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>Autosomal Dominant Dopa-Responsive Dystonia</em></strong></p><p>
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In affected members of 4 families with autosomal dominant dopa-responsive dystonia (DRD) (DYT5; <a href="/entry/128230">128230</a>), <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> identified 4 heterozygous mutations in the GCH1 gene (<a href="#0001">600225.0001</a>-<a href="#0004">600225.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" 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>Among 36 cases of dopamine-responsive dystonia, including 33 cases from 9 British families and 3 sporadic cases, <a href="#1" class="mim-tip-reference" title="Bandmann, O., Nygaard, T. G., Surtees, R., Marsden, C. D., Wood, N. W., Harding, A. E. <strong>Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity.</strong> Hum. Molec. Genet. 5: 403-406, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852666</a>] [<a href="https://doi.org/10.1093/hmg/5.3.403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8852666">Bandmann et al. (1996)</a> identified 6 novel mutations in the GCH1 gene, all of which were point mutations. In 4 families and 2 sporadic cases, no mutations were identified, suggesting genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8852666" 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="#24" class="mim-tip-reference" title="Skrygan, M., Bartholome, B., Bonafe, L., Blau, N., Bartholome, K. <strong>A splice mutation in the GTP cyclohydrolase I gene causes dopa-responsive dystonia by exon skipping.</strong> J. Inherit. Metab. Dis. 24: 345-351, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486899</a>] [<a href="https://doi.org/10.1023/a:1010544316387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486899">Skrygan et al. (2001)</a> identified 4 different mutations in the GCH1 gene (see, e.g., <a href="#0019">600225.0019</a>) in 6 of 33 families with dopa-responsive dystonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486899" 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="Hagenah, J., Saunders-Pullman, R., Hedrich, K., Kabakci, K., Habermann, K., Wiegers, K., Mohrmann, K., Lohnau, T., Raymond, D., Vieregge, P., Nygaard, T., Ozelius, L. J., Bressman, S. B., Klein, C. <strong>High mutation rate in dopa-responsive dystonia: detection with comprehensive GCH1 screening.</strong> Neurology 64: 908-911, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15753436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15753436</a>] [<a href="https://doi.org/10.1212/01.WNL.0000152839.50258.A2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15753436">Hagenah et al. (2005)</a> identified mutations in the GCH1 gene in 20 (87%) of 23 unrelated individuals with dopa-responsive dystonia. Two patients had large deletions of more than 1 exon, which were detected only by quantitative PCR testing. <a href="#9" class="mim-tip-reference" title="Hagenah, J., Saunders-Pullman, R., Hedrich, K., Kabakci, K., Habermann, K., Wiegers, K., Mohrmann, K., Lohnau, T., Raymond, D., Vieregge, P., Nygaard, T., Ozelius, L. J., Bressman, S. B., Klein, C. <strong>High mutation rate in dopa-responsive dystonia: detection with comprehensive GCH1 screening.</strong> Neurology 64: 908-911, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15753436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15753436</a>] [<a href="https://doi.org/10.1212/01.WNL.0000152839.50258.A2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15753436">Hagenah et al. (2005)</a> stated that 85 different mutations had been reported in the GCH1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15753436" 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="#27" class="mim-tip-reference" title="Steinberger, D., Trubenbach, J., Zirn, B., Leube, B., Wildhardt, G., Muller, U. <strong>Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia.</strong> Neurogenetics 8: 51-55, 2007. Note: Erratum: Neurogenetics 8: 69 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17111153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17111153</a>] [<a href="https://doi.org/10.1007/s10048-006-0069-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17111153">Steinberger et al. (2007)</a> used multiple ligation-dependent probe amplification (MLPA) to examine exons 1, 2, 3, 5, and 6 of the GCH1 gene in affected members of 3 unrelated families with DRD who did not have single basepair changes. The authors identified 3 different large heterozygous GCH1 deletions, including deletion of the entire gene (<a href="#0021">600225.0021</a>). The findings demonstrated that DRD is most likely due to haploinsufficiency of the GCH1 gene, rather than a dominant-negative effect. All patients showed characteristic signs and symptoms of DRD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17111153" 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>BH4-Deficient Hyperphenylalaninemia B</em></strong></p><p>
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In a male infant with GCH1 deficiency manifest as hyperphenylalaninemia (HPABH4B; <a href="/entry/233910">233910</a>), <a href="#2" class="mim-tip-reference" title="Blau, N., Ichinose, H., Nagatsu, T., Heizmann, C. W., Zacchello, F., Burlina, A. B. <strong>A missense mutation in a patient with guanosine triphosphate cyclohydrolase I deficiency missed in the newborn screening program.</strong> J. Pediat. 126: 401-405, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7869202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7869202</a>] [<a href="https://doi.org/10.1016/s0022-3476(95)70458-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7869202">Blau et al. (1995)</a> identified a homozygous mutation in the GCH1 gene (<a href="#0017">600225.0017</a>). In another patient with GCH1 deficiency, <a href="#16" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> identified a homozygous mutation in the GCH1 gene (<a href="#0020">600225.0020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7730309+7869202" 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>Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. <strong>Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.</strong> Ann. Neurol. 44: 10-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667588</a>] [<a href="https://doi.org/10.1002/ana.410440107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667588">Furukawa et al. (1998)</a>, <a href="#14" class="mim-tip-reference" title="Hwu, W.-L., Wang, P.-J., Hsiao, K.-J., Wang, T.-R., Chiou, Y.-W., Lee, Y.-M. <strong>Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation.</strong> Hum. Genet. 105: 226-230, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987649</a>] [<a href="https://doi.org/10.1007/s004390051093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987649">Hwu et al. (1999)</a>, and <a href="#23" class="mim-tip-reference" title="Nardocci, N., Zorzi, G., Blau, N., Alvarez, E. F., Sesta, M., Angelini, L., Pannacci, M., Invernizzi, F., Garavaglia, B. <strong>Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency.</strong> Neurology 60: 335-337, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12552057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12552057</a>] [<a href="https://doi.org/10.1212/01.wnl.0000044049.99690.ad" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12552057">Nardocci et al. (2003)</a> identified homozygous or compound heterozygous mutations in patients with dopa-responsive dystonia with or without hyperphenylalaninemia (see, e.g., <a href="#0010">600225.0010</a>, <a href="#0016">600225.0016</a>, and <a href="#0022">600225.0022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9667588+12552057+10987649" 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>There is a 4:1 female predominance in dopa-responsive dystonia. <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> found higher GTP cyclohydrolase I activities in males than in females, a possible explanation for the difference in frequency of the disorder. The diurnal fluctuations that are characteristic of this disorder may be explained by the relatively short half-life of BH4. Patients with heterozygous mutations in the GCH1 gene may synthesize BH4 at a low rate that is not high enough to compensate for the consumption of the cofactor during the day, thus leading to aggravation of symptoms toward evening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" 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="#10" class="mim-tip-reference" title="Hirano, M., Imaiso, Y., Ueno, S. <strong>Differential splicing of the GTP cyclohydrolase I RNA in dopa-responsive dystonia.</strong> Biochem. Biophys. Res. Commun. 234: 316-319, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177267</a>] [<a href="https://doi.org/10.1006/bbrc.1997.6632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9177267">Hirano et al. (1997)</a> studied a mutation in the GCH1 gene suggesting that the abnormal polypeptide encoded by mutant RNA interacts with wildtype polypeptides, generating nonfunctional heteromultimers. They suggested that more frequent occurrence of DYT5 in females than in males may be explained by the higher basal levels of the enzyme in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9177267" 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 patients with dopa-responsive dystonia, <a href="#22" class="mim-tip-reference" title="Muller, U., Steinberger, D., Nemeth, A. H. <strong>Clinical and molecular genetics of primary dystonias.</strong> Neurogenetics 1: 165-177, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737119</a>] [<a href="https://doi.org/10.1007/s100480050025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737119">Muller et al. (1998)</a> tabulated 29 separate mutations in the GCH1 gene. Most of the mutations resulted in truncation of the enzyme, due to the introduction of a stop codon, a frameshift mutation, or abnormal splicing. Patients who were heterozygous for GCH1 mutations developed dopa-responsive dystonia, whereas individuals who were homozygous or compound heterozygous for GCH1 mutations developed hyperphenylalaninemia with accompanying deficiency of dopamine and serotonin. The authors concluded that autosomal dominant dopa-responsive dystonia is not likely to be simply a matter of haploinsufficiency of the enzyme, because patients with DYT5 have enzyme levels that are approximately 20% of normal rather than the expected 50%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tamaru, Y., Hirano, M., Ito, H., Kawamura, J., Matsumoto, S., Imai, T., Ueno, S. <strong>Clinical similarities of hereditary progressive/dopa responsive dystonia caused by different types of mutations in the GTP cyclohydrolase I gene.</strong> J. Neurol. Neurosurg. Psychiat. 64: 469-473, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9576537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9576537</a>] [<a href="https://doi.org/10.1136/jnnp.64.4.469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9576537">Tamaru et al. (1998)</a> studied the GCH1 gene and the clinical features of 8 patients from 6 families with hereditary progressive dystonia with pronounced diurnal fluctuation/dopa-responsive dystonia. Three independent GCH1 mutations were found in 3 patients. One of the patients and her asymptomatic mother were heterozygous for a novel mutation at the initiation codon. The 3 patients with dissimilar GCH1 mutations showed similar clinical features, including isolated limb dystonia progressing to generalized dystonia, diurnal fluctuation of symptoms, and favorable response to levodopa. The other 5 patients with normal sequences in the GCH1 gene presented several features not manifested by the 3 patients with the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9576537" 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 members of a Japanese family with hereditary progressive dystonia with marked diurnal fluctuation, but no mutation in the coding region or splice junctions of the GCH1 gene, <a href="#18" class="mim-tip-reference" title="Inagaki, H., Ohye, T., Suzuki, T., Segawa, M., Nomura, Y., Nagatsu, T., Ichinose, H. <strong>Decrease in GTP cyclohydrolase I gene expression caused by inactivation of one allele in hereditary progressive dystonia with marked diurnal fluctuation.</strong> Biochem. Biophys. Res. Commun. 260: 747-751, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10403837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10403837</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10403837">Inagaki et al. (1999)</a> quantified the mRNA levels of GCH1 in phytohemagglutinin-stimulated mononuclear blood cells. They found that the amounts of GCH1 mRNA were decreased to about 40% of the normal level in both patients and carriers. In addition, they found that the GCH1 mRNA was transcribed from only 1 allele, indicating that the other allele was in an inactive state. These results suggested that some novel mutations exist on 1 of the alleles in an unknown region of the GCH1 gene and may decrease the GCH1 mRNA, causing the manifestations of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10403837" 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>Among 58 patients with dopa-responsive dystonia, <a href="#25" class="mim-tip-reference" title="Steinberger, D., Korinthenberg, R., Topka, H., Berghauser, M., Wedde, R., Muller, U. <strong>Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa.</strong> Neurology 55: 1735-1737, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113234</a>] [<a href="https://doi.org/10.1212/wnl.55.11.1735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113234">Steinberger et al. (2000)</a> identified mutations in the GCH1 gene in 30 individuals from 22 families. Thirteen of the mutations were familial, 3 occurred de novo, and inheritance could not be determined in 6 cases. Four novel mutations were identified, including a missense mutation, a frameshift mutation, and 2 intronic mutations that affected donor splice sites. Since there was no difference in therapeutic doses of L-DOPA between patients with or without a GCH1 mutation, the authors suggested that the phenotype may be caused by other genes involved in the synthesis of dopamine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113234" 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>Among 168 Caucasian adults, <a href="#29" class="mim-tip-reference" title="Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., Ehnert, C., Nejim, J., Marian, C., Scholz, J., Wu, T., Allchorne, A., and 14 others. <strong>GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.</strong> Nature Med. 12: 1269-1277, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17057711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17057711</a>] [<a href="https://doi.org/10.1038/nm1490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17057711">Tegeder et al. (2006)</a> found that a GCH1 haplotype (allelic frequency of 15%) causing decreased enzyme levels was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and stimulated immortalized leukocytes from haplotype carriers showed decreased upregulation of GCH1 compared to controls. Based on these findings and rodent models, <a href="#29" class="mim-tip-reference" title="Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., Ehnert, C., Nejim, J., Marian, C., Scholz, J., Wu, T., Allchorne, A., and 14 others. <strong>GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.</strong> Nature Med. 12: 1269-1277, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17057711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17057711</a>] [<a href="https://doi.org/10.1038/nm1490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17057711">Tegeder et al. (2006)</a> concluded that alterations in the concentration of BH4 due to GCH1 activity modify pain sensitivity and susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17057711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The Hph1 mouse exhibits hyperphenylalaninemia and a reduction in GTP cyclohydrolase I activity (<a href="#20" class="mim-tip-reference" title="McDonald, J. D., Cotton, R. J. H., Jennings, I., Ledley, F. D., Woo, S. L. C., Bode, V. C. <strong>Biochemical defect of hph-1 mouse mutant is a deficiency in GTP-cyclohydrolase activity.</strong> J. Neurochem. 50: 655-657, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3335865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3335865</a>] [<a href="https://doi.org/10.1111/j.1471-4159.1988.tb02961.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3335865">McDonald et al., 1988</a>). <a href="#3" class="mim-tip-reference" title="Bode, V. C., McDonald, J. D., Guenet, J.-L., Simon, D. <strong>Hph-1: a mouse mutant with hereditary hyperphenylalaninemia induced by ethylnitrosourea mutagenesis.</strong> Genetics 118: 299-305, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3360305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3360305</a>] [<a href="https://doi.org/10.1093/genetics/118.2.299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3360305">Bode et al. (1988)</a> showed that the Hph1 gene in the mouse is tightly linked to the nucleoside phosphorylase gene (PNP; <a href="/entry/164050">164050</a>) on chromosome 14. This region shows syntenic homology with the region of human chromosome 14 containing the GCH1 and PNP genes. <a href="#16" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> mapped the mouse Gch gene to region C2-C3 of chromosome 14 by in situ hybridization. <a href="#21" class="mim-tip-reference" title="Montanez, C. S., McDonald, J. D. <strong>Linkage analysis of the hph-1 mutation and the GTP cyclohydrolase I structural gene.</strong> Molec. Genet. Metab. 68: 91-92, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10479487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10479487</a>] [<a href="https://doi.org/10.1006/mgme.1999.2887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10479487">Montanez and McDonald (1999)</a> demonstrated linkage between the hph1 mutation and the Gch locus on mouse chromosome 14, supporting the use of the hph1 mouse mutant as a bona fide model system for the human disorder of GTP cyclohydrolase I deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3335865+3360305+7730309+10479487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hyland, K., Gunasekara, R. S., Munk-Martin, T. L., Arnold, L. A., Engle, T. <strong>The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency.</strong> Ann. Neurol. 54: S46-S48, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12891653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12891653</a>] [<a href="https://doi.org/10.1002/ana.10695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12891653">Hyland et al. (2003)</a> found that hph1 mice have low brain levels of BH4, catecholamines, serotonin, and their metabolites, together with low levels of tyrosine hydroxylase protein within the striatum. These findings are similar to the neurochemical findings in human patients with mutations in the GCH1 gene, suggesting that the hph1 mouse is a good model system of GCH1 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12891653" 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 rodent models of neuropathic and inflammatory pain, <a href="#29" class="mim-tip-reference" title="Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., Ehnert, C., Nejim, J., Marian, C., Scholz, J., Wu, T., Allchorne, A., and 14 others. <strong>GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.</strong> Nature Med. 12: 1269-1277, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17057711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17057711</a>] [<a href="https://doi.org/10.1038/nm1490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17057711">Tegeder et al. (2006)</a> found an increase of BH4 resulting from upregulation or enhanced enzyme activity of Gch1. Inhibition of BH4 synthesis by blocking Gch1 activity resulted in attenuation of the pain and prevented nerve injury-evoked excess nitric oxide production, whereas administration of BH4 exacerbated pain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17057711" 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 family with progressive dystonia with diurnal variation (<a href="/entry/128230">128230</a>), also known as dopa-responsive dystonia, <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> identified a heterozygous C-T transition in the GCH1 gene, resulting in an arg88-to-trp substitution (R88W). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" 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 family with progressive dystonia with diurnal variation (<a href="/entry/128230">128230</a>), <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> identified a heterozygous A-T transversion in the GCH1 gene, resulting in an asp134-to-val (D134V) substitution of valine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" 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">rs2140127822 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140127822;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=rs2140127822" 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=rs2140127822" 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=RCV000009855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009855</a>
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<p>In affected members of a family with progressive dystonia with marked diurnal fluctuation (<a href="/entry/128230">128230</a>), <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> identified a heterozygous 2-bp insertion in the GCH1 gene, leading to a frameshift and a premature stop codon at position 197. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0004 DYSTONIA, DOPA-RESPONSIVE</strong>
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GCH1, GLY201GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894438 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894438;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=rs104894438" 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=rs104894438" 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=RCV000009856" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009856" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009856</a>
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<p>In affected members of a family with progressive dystonia with diurnal variation (<a href="/entry/128230">128230</a>), <a href="#17" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., Nagatsu, T. <strong>Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.</strong> Nature Genet. 8: 236-242, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874165</a>] [<a href="https://doi.org/10.1038/ng1194-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874165">Ichinose et al. (1994)</a> identified a heterozygous G-A transition in the GCH1 gene, resulting in a gly201-to-glu (G201E) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874165" 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 vitro, <a href="#12" class="mim-tip-reference" title="Hwu, W.-L., Chiou, Y.-W., Lai, S.-Y., Lee, Y.-M. <strong>Dopa-responsive dystonia is induced by a dominant-negative mechanism.</strong> Ann. Neurol. 48: 609-613, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11026444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11026444</a>]" pmid="11026444">Hwu et al. (2000)</a> found that expression of the G201E mutation resulted in rapid degradation of the GCH1 protein with approximately 5% enzyme activity. Cotransfection studies showed that the G201E mutation interacted with the wildtype protein, decreasing its level and activity. <a href="#12" class="mim-tip-reference" title="Hwu, W.-L., Chiou, Y.-W., Lai, S.-Y., Lee, Y.-M. <strong>Dopa-responsive dystonia is induced by a dominant-negative mechanism.</strong> Ann. Neurol. 48: 609-613, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11026444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11026444</a>]" pmid="11026444">Hwu et al. (2000)</a> concluded that the G201E mutation exerts a dominant-negative effect, either by inhibition or destabilization. Similar studies with R249S (<a href="#0016">600225.0016</a>) showed no dominant-negative effect, consistent with a recessive dopa-responsive dystonia mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11026444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0005 DYSTONIA, DOPA-RESPONSIVE</strong>
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</h4>
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GCH1, IVS1, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2140074226 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140074226;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=rs2140074226" 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=rs2140074226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009857" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009857" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009857</a>
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<span class="mim-text-font">
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<p>In patients with dopa-responsive dystonia (<a href="/entry/128230">128230</a>), <a href="#32" class="mim-tip-reference" title="Weber, Y., Steinberger, D., Deuschl, G., Benecke, R., Muller, U. <strong>Two previously unrecognized splicing mutations of GCH1 in dopa-responsive dystonia: exon skipping and one base insertion.</strong> Neurogenetics 1: 125-127, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732814</a>] [<a href="https://doi.org/10.1007/s100480050018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732814">Weber et al. (1997)</a> identified 2 previously unrecognized splice site mutations of GCH1 which affected consensus splice acceptor (AG) sites. The first mutation was an A-G transition at position -2 of intron 1 of GCH1, predicted to result in the skipping of exon 2. Fusion of exons 1 and 3 caused a frameshift that generated a premature stop codon. The second mutation was an A-G transition at position -2 of intron 2 (<a href="#0006">600225.0006</a>), predicted to generated a new splice acceptor site 1 basepair upstream of the wildtype splice site. This, together with a pyrimidine stretch upstream of the new splice site, rendered this site functional and generated a transcript with the insertion of 1 base, i.e., the G of the wildtype splice site. This in turn caused a frameshift, including the introduction of a premature stop codon. Both mutations generated truncated GTP cyclohydrolase polypeptides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 DYSTONIA, DOPA-RESPONSIVE</strong>
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GCH1, IVS2, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2039866854 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2039866854;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=rs2039866854" 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=rs2039866854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001091044 OR RCV001824413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001091044, RCV001824413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001091044...</a>
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<span class="mim-text-font">
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<p>See <a href="#0005">600225.0005</a> and <a href="#32" class="mim-tip-reference" title="Weber, Y., Steinberger, D., Deuschl, G., Benecke, R., Muller, U. <strong>Two previously unrecognized splicing mutations of GCH1 in dopa-responsive dystonia: exon skipping and one base insertion.</strong> Neurogenetics 1: 125-127, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732814</a>] [<a href="https://doi.org/10.1007/s100480050018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732814">Weber et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<strong>.0007 DYSTONIA, DOPA-RESPONSIVE</strong>
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</h4>
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GCH1, MET1ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894439 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894439;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=rs104894439" 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=rs104894439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009859" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009859" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009859</a>
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<p>In a 36-year-old woman with DYT5 (<a href="/entry/128230">128230</a>) and her asymptomatic mother, <a href="#28" class="mim-tip-reference" title="Tamaru, Y., Hirano, M., Ito, H., Kawamura, J., Matsumoto, S., Imai, T., Ueno, S. <strong>Clinical similarities of hereditary progressive/dopa responsive dystonia caused by different types of mutations in the GTP cyclohydrolase I gene.</strong> J. Neurol. Neurosurg. Psychiat. 64: 469-473, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9576537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9576537</a>] [<a href="https://doi.org/10.1136/jnnp.64.4.469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9576537">Tamaru et al. (1998)</a> found heterozygosity for a G-C transversion in the initiation codon of the GCH1 gene, causing a met1-to-ile (M1I) substitution. The mutation abolished the first AUG codon. The next AUG codon lies at the position corresponding to amino acid 20, resulting in a frameshift and a UGA termination codon located 139 nucleotides downstream. The putative translation product was a 46-amino acid peptide completely different from the normal GCH1 gene product. The patient had had intermittent internal rotation of her legs, particularly the left, since the age of 8. The symptoms were aggravated toward evening and gradually spread to the other limbs. Postural tremor became apparent after the age of 20. During her thirties, she could walk for 1 hour in the morning, becoming immobile toward evening. At examination at the age of 35, both feet tended to turn inward and plantarflex. She walked with her left foot circumflexed. Small doses of levodopa provided a considerable and sustained improvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9576537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 DYSTONIA, DOPA-RESPONSIVE</strong>
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</span>
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GCH1, HIS144PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894440 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894440;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=rs104894440" 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=rs104894440" 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=RCV000009860" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009860" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009860</a>
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<p>In a 26-year-old woman with DYT5 (<a href="/entry/128230">128230</a>) and her asymptomatic father, <a href="#28" class="mim-tip-reference" title="Tamaru, Y., Hirano, M., Ito, H., Kawamura, J., Matsumoto, S., Imai, T., Ueno, S. <strong>Clinical similarities of hereditary progressive/dopa responsive dystonia caused by different types of mutations in the GTP cyclohydrolase I gene.</strong> J. Neurol. Neurosurg. Psychiat. 64: 469-473, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9576537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9576537</a>] [<a href="https://doi.org/10.1136/jnnp.64.4.469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9576537">Tamaru et al. (1998)</a> found heterozygosity for a his144-to-pro (H144P) missense mutation of the GCH1 gene. The patient had developed knee disturbances at the age of 7 due to pes equinovarus of both legs, dominantly in the left one. Her head turned involuntarily to the right, which worsened in the afternoon. When she was 18 years old, she noted clumsiness of the hands due to postural tremor. Her symptoms were completely controlled after she started levodopa therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9576537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 DYSTONIA, DOPA-RESPONSIVE</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">rs2140073990 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140073990;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=rs2140073990" 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=rs2140073990" 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=RCV000009861 OR RCV001851775" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009861, RCV001851775" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009861...</a>
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<p>In a 23-year-old man with DYT5 (<a href="/entry/128230">128230</a>) and his asymptomatic mother, <a href="#28" class="mim-tip-reference" title="Tamaru, Y., Hirano, M., Ito, H., Kawamura, J., Matsumoto, S., Imai, T., Ueno, S. <strong>Clinical similarities of hereditary progressive/dopa responsive dystonia caused by different types of mutations in the GTP cyclohydrolase I gene.</strong> J. Neurol. Neurosurg. Psychiat. 64: 469-473, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9576537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9576537</a>] [<a href="https://doi.org/10.1136/jnnp.64.4.469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9576537">Tamaru et al. (1998)</a> found heterozygosity for a G-C transversion at the 5-prime end of intron 2 of GCH1, causing the skipping of exon 1 to exon 3. The man had first noticed flexion-inversion of the right foot, especially in the afternoon, at the age of 10 years. His dystonia gradually progressed to involve all limbs within 5 years, but was more pronounced in the lower limbs. At the age of 22 years, he showed pronounced dystonic posturing in the left hand and leg as well as scoliosis. He walked on his toes with torticollis to the left and carried his left arm in the flexed position. After the initiation of levodopa therapy, his symptoms improved remarkably. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9576537" 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 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</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">rs2140074192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140074192;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=rs2140074192" 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=rs2140074192" 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=RCV002508111" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002508111" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002508111</a>
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<p>In a 6-year-old girl with dopa-responsive dystonia (see <a href="/entry/233910">233910</a>), <a href="#6" class="mim-tip-reference" title="Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. <strong>Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.</strong> Ann. Neurol. 44: 10-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667588</a>] [<a href="https://doi.org/10.1002/ana.410440107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667588">Furukawa et al. (1998)</a> identified a 1-bp deletion in exon 2 of the GCH1 gene. Her mother, maternal grandmother, and great-grandmother, all of whom had progressive dystonia with diurnal variation, also carried the same deletion. Only the proband with motor delay was a compound heterozygote for an additional mutation, a T-C transition in exon 6, resulting in a met221-to-thr substitution (<a href="#0011">600225.0011</a>), which she had inherited from her asymptomatic father. The proband responded to treatment with tetrahydrobiopterin and levodopa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9667588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</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> rs104894434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894434;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/rs104894434?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=rs104894434" 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=rs104894434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001260617 OR RCV001851776 OR RCV002223756 OR RCV002508112 OR RCV004766995 OR RCV004786251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001260617, RCV001851776, RCV002223756, RCV002508112, RCV004766995, RCV004786251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001260617...</a>
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<p>See <a href="#0010">600225.0010</a> and <a href="#6" class="mim-tip-reference" title="Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. <strong>Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.</strong> Ann. Neurol. 44: 10-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667588</a>] [<a href="https://doi.org/10.1002/ana.410440107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667588">Furukawa et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9667588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</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">rs104894435 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894435;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=rs104894435" 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=rs104894435" 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=RCV000634833 OR RCV001659690 OR RCV002508113" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000634833, RCV001659690, RCV002508113" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000634833...</a>
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<p>In a 17-year-old male with dopa-responsive dystonia (see <a href="/entry/233910">233910</a>) <a href="#6" class="mim-tip-reference" title="Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. <strong>Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.</strong> Ann. Neurol. 44: 10-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667588</a>] [<a href="https://doi.org/10.1002/ana.410440107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667588">Furukawa et al. (1998)</a> identified a novel G-A transition in exon 1 of the GCH1 gene, resulting in a gly108-to-asp (G108D) substitution, which was inherited from his asymptomatic father, who was not examined. The patient was a compound heterozygote for an additional mutation in the GCH1 gene, an A-G transition in exon 6, resulting in a lys224-to-arg (K224R) substitution (<a href="#0013">600225.0013</a>), which he had inherited from his asymptomatic mother. The boy could not walk until age 4, at which time language was normal except for mild dysarthria. Between the ages of 4 and 6 years, the patient's previously acquired motor and speech functions deteriorated, and he subsequently became wheelchair bound and mute. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9667588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<strong>.0013 DYSTONIA, DOPA-RESPONSIVE</strong>
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DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE, INCLUDED
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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> rs41298442 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41298442;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/rs41298442?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=rs41298442" 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=rs41298442" 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=RCV000009865 OR RCV000517539 OR RCV000525589 OR RCV000989227 OR RCV002255090 OR RCV002508114 OR RCV002512951 OR RCV005003351" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009865, RCV000517539, RCV000525589, RCV000989227, RCV002255090, RCV002508114, RCV002512951, RCV005003351" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009865...</a>
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<p>See <a href="#0012">600225.0012</a> and <a href="#6" class="mim-tip-reference" title="Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. <strong>Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.</strong> Ann. Neurol. 44: 10-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667588</a>] [<a href="https://doi.org/10.1002/ana.410440107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667588">Furukawa et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9667588" 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="#19" class="mim-tip-reference" title="Leuzzi, V., Carducci, C., Carducci, C., Cardona, F., Artiola, C., Antonozzi, I. <strong>Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome.</strong> Neurology 59: 1241-1243, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391354</a>] [<a href="https://doi.org/10.1212/wnl.59.8.1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391354">Leuzzi et al. (2002)</a> reported a consanguineous Italian family in which 5 members over 3 generations were affected with variable severity of dopa-responsive dystonia (<a href="/entry/128230">128230</a>) with features of a myoclonus-dystonia syndrome (see, e.g., <a href="/entry/159900">159900</a>). The most severely affected individual was the proband, the son of first cousins, who developed progressive myoclonic jerky movements of his upper limbs, lower limbs, trunk, and face beginning at the age of 3 years. He also exhibited mild dystonic postures of the upper limbs and neck, mild bradykinesia, and lack of facial expression. Blood prolactin was elevated and CSF homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), and biopterin were reduced. Treatment with L-DOPA resulted in marked improvement. In 4 affected members who were tested, including the proband, <a href="#19" class="mim-tip-reference" title="Leuzzi, V., Carducci, C., Carducci, C., Cardona, F., Artiola, C., Antonozzi, I. <strong>Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome.</strong> Neurology 59: 1241-1243, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391354</a>] [<a href="https://doi.org/10.1212/wnl.59.8.1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391354">Leuzzi et al. (2002)</a> identified a heterozygous 671A-G missense mutation in the GCH1 gene, resulting in a lys224-to-arg (L224R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391354" 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 DYSTONIA, DOPA-RESPONSIVE</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> rs104894436 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894436;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/rs104894436?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=rs104894436" 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=rs104894436" 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=RCV000009867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009867</a>
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<p><a href="#26" class="mim-tip-reference" title="Steinberger, D., Topka, H., Fischer, D., Muller, U. <strong>GCH1 mutation in a patient with adult-onset oromandibular dystonia.</strong> Neurology 52: 877-879, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078749</a>] [<a href="https://doi.org/10.1212/wnl.52.4.877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078749">Steinberger et al. (1999)</a> reported a 49-year-old male with a 3-year history of dopa-responsive dystonia (<a href="/entry/128230">128230</a>) manifested mainly as an oromandibular dystonia involving involuntary movements of the tongue and lips which worsened during exercise. The patient also showed subtle abnormal posturing of his right hand when he wrote with his left. The oromandibular dystonia partially responded to treatment with levodopa and benserazide. The patient's family history revealed no obvious cases of dystonia, although his father reportedly had abnormal facial movements in childhood that disappeared during adolescence. By DNA analysis, <a href="#26" class="mim-tip-reference" title="Steinberger, D., Topka, H., Fischer, D., Muller, U. <strong>GCH1 mutation in a patient with adult-onset oromandibular dystonia.</strong> Neurology 52: 877-879, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078749</a>] [<a href="https://doi.org/10.1212/wnl.52.4.877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078749">Steinberger et al. (1999)</a> identified a novel 586G-T transversion in exon 5 of the GCH1 gene, resulting in an ala196-to-ser (A196S) substitution. They also identified a synonymous mutation, a 582G-A transition in exon 5, on the same chromosome as the presumed pathogenic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10078749" 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>.0015 DYSTONIA, DOPA-RESPONSIVE</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">rs104894441 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894441;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=rs104894441" 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=rs104894441" 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=RCV000009868" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009868" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009868</a>
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<p>In a French family with 4 sibs affected with juvenile-onset dopa-responsive dystonia and simultaneous or later-onset parkinsonism (<a href="/entry/128230">128230</a>), <a href="#4" class="mim-tip-reference" title="Brique, S., Destee, A., Lambert, J.-C., Mouroux, V., Delacourte, A., Amouyel, P., Chartier-Harlin, M.-C. <strong>A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form.</strong> Neuroreport 10: 487-491, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208576</a>] [<a href="https://doi.org/10.1097/00001756-199902250-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10208576">Brique et al. (1999)</a> found heterozygosity for an A-T transversion in exon 2 of the GCH1 gene, resulting in an ile135-to-lys (I135K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208576" 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>.0016 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</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> rs104894442 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894442;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/rs104894442?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=rs104894442" 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=rs104894442" 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=RCV000518763 OR RCV002508115" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000518763, RCV002508115" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000518763...</a>
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<p><a href="#14" class="mim-tip-reference" title="Hwu, W.-L., Wang, P.-J., Hsiao, K.-J., Wang, T.-R., Chiou, Y.-W., Lee, Y.-M. <strong>Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation.</strong> Hum. Genet. 105: 226-230, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987649</a>] [<a href="https://doi.org/10.1007/s004390051093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987649">Hwu et al. (1999)</a> described a girl with progressive dopa-responsive dystonia with diurnal fluctuation (see <a href="/entry/233910">233910</a>) beginning at age 2 years and 8 months. There was no family history of the disorder. Plasma phenylalanine was normal. Genetic analysis identified a homozygous 747C-G transversion in the GCH1 gene, resulting in an arg249-to-ser (R249S) substitution. The patient's cells had low, but measurable enzyme activity, compatible with dopa-responsive dystonia. Arginine-249 is located at the C terminus of the protein, outside the catalytic site. E. coli-expressed recombinant R249S mutant protein possessed normal enzyme activity and kinetics. However, in transfected eukaryotic cells, the expression level of the R249S mutant protein was lower than that of the wildtype protein. Therefore, <a href="#14" class="mim-tip-reference" title="Hwu, W.-L., Wang, P.-J., Hsiao, K.-J., Wang, T.-R., Chiou, Y.-W., Lee, Y.-M. <strong>Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation.</strong> Hum. Genet. 105: 226-230, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987649</a>] [<a href="https://doi.org/10.1007/s004390051093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987649">Hwu et al. (1999)</a> suspected that R249S is a destabilizing mutation. Both parents were heterozygous for the mutation, and only mutant clones could be found in the patient, whereas both the mutant and wildtype forms were found in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10987649" 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>.0017 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B</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">rs104894443 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894443;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=rs104894443" 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=rs104894443" 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=RCV004576896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576896</a>
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<p>In a male infant with BH4-dependent hyperphenylalaninemia due to GCH1 deficiency (HPABH4B; <a href="/entry/233910">233910</a>), <a href="#16" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> and <a href="#2" class="mim-tip-reference" title="Blau, N., Ichinose, H., Nagatsu, T., Heizmann, C. W., Zacchello, F., Burlina, A. B. <strong>A missense mutation in a patient with guanosine triphosphate cyclohydrolase I deficiency missed in the newborn screening program.</strong> J. Pediat. 126: 401-405, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7869202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7869202</a>] [<a href="https://doi.org/10.1016/s0022-3476(95)70458-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7869202">Blau et al. (1995)</a> identified a homozygous G-to-A transition in the GCH1 gene, resulting in a met211-to-ile (M211I) substitution. In vitro functional expression studies in E. coli showed that the mutant protein lacked enzymatic activity. The patient had progressive neurologic symptoms, including hypotonia and uncoordinated movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7730309+7869202" 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>.0018 DYSTONIA, DOPA-RESPONSIVE</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">rs104894444 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894444;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=rs104894444" 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=rs104894444" 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=RCV000009871 OR RCV001390287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009871, RCV001390287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009871...</a>
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<p>In affected members of a Korean family with dopa-responsive dystonia (<a href="/entry/128230">128230</a>), <a href="#11" class="mim-tip-reference" title="Hong, K.-M., Kim, Y.-S., Paik, M.-K. <strong>A novel nonsense mutation of the GTP cyclohydrolase I gene in a family with dopa-responsive dystonia.</strong> Hum. Hered. 52: 59-60, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359069</a>] [<a href="https://doi.org/10.1159/000053355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359069">Hong et al. (2001)</a> identified a heterozygous 142C-T transition in exon 1 of the GCH1 gene, resulting in nonsense mutation (gln48-to-ter; Q48X). Two sisters and 3 of their children were affected and carried the mutation. Expression was milder in the 1 male of the 5 symptomatic relatives; 3 individuals in another branch of the family carried the mutation but were asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 DYSTONIA, DOPA-RESPONSIVE</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">rs1555358507 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555358507;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=rs1555358507" 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=rs1555358507" 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=RCV000634835 OR RCV001090536 OR RCV001836648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000634835, RCV001090536, RCV001836648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000634835...</a>
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<p>In an individual with dopa-responsive dystonia (<a href="/entry/128230">128230</a>), <a href="#24" class="mim-tip-reference" title="Skrygan, M., Bartholome, B., Bonafe, L., Blau, N., Bartholome, K. <strong>A splice mutation in the GTP cyclohydrolase I gene causes dopa-responsive dystonia by exon skipping.</strong> J. Inherit. Metab. Dis. 24: 345-351, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486899</a>] [<a href="https://doi.org/10.1023/a:1010544316387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486899">Skrygan et al. (2001)</a> identified a G-A transition at IVS5+1. Three members of the family carried the mutation, which was inherited from the father to the daughter and son, but only 1 was symptomatic. Examination of the mRNA showed an exon 5 skipping that results in reduction of the enzyme activity in cultured fibroblasts to 4 to 17% compared to controls. The son was symptomatic at the age of 3 years and was successfully treated with L-DOPA/carbidopa. After 20 years, this therapy was terminated and for the next 6 years he was free of symptoms. With increased motor activity, symptoms reappeared and the therapy was reintroduced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B</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">rs104894445 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894445;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=rs104894445" 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=rs104894445" 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=RCV000009873 OR RCV003137509 OR RCV003764543 OR RCV004576897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009873, RCV003137509, RCV003764543, RCV004576897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009873...</a>
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<p>In a girl with BH4-dependent hyperphenylalaninemia due to GTP cyclohydrolase I deficiency (<a href="/entry/233910">233910</a>), <a href="#16" class="mim-tip-reference" title="Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. <strong>Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency.</strong> J. Biol. Chem. 270: 10062-10071, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7730309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7730309</a>] [<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7730309">Ichinose et al. (1995)</a> identified a homozygous G-A change in the GCH1 gene, resulting in an arg184-to-his (R184H) substitution. Functional expression studies showed that the mutation caused a loss of enzyme activity. She developed feeding problems, poor sucking, and poor muscle tone in the first week of life, and later showed delayed development. By the age of 2 years, the child was unable to walk and developed seizures and choreoathetosis. Urinary pterins showed a profound deficiency in neopterin and biopterin. She died at age 10 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7730309" 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>.0021 DYSTONIA, DOPA-RESPONSIVE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009874</a>
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<p>In 3 affected members of a 2-generation family with DRD (<a href="/entry/128230">128230</a>), <a href="#27" class="mim-tip-reference" title="Steinberger, D., Trubenbach, J., Zirn, B., Leube, B., Wildhardt, G., Muller, U. <strong>Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia.</strong> Neurogenetics 8: 51-55, 2007. Note: Erratum: Neurogenetics 8: 69 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17111153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17111153</a>] [<a href="https://doi.org/10.1007/s10048-006-0069-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17111153">Steinberger et al. (2007)</a> identified a heterozygous complete deletion of the GCH1 gene. The findings suggested that the phenotype results from haploinsufficiency rather than a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17111153" 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>.0022 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</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">rs137852633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852633;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=rs137852633" 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=rs137852633" 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=RCV002508116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002508116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002508116</a>
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<p>In monozygotic twin girls with onset of extrapyramidal features in the first months of life, <a href="#23" class="mim-tip-reference" title="Nardocci, N., Zorzi, G., Blau, N., Alvarez, E. F., Sesta, M., Angelini, L., Pannacci, M., Invernizzi, F., Garavaglia, B. <strong>Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency.</strong> Neurology 60: 335-337, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12552057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12552057</a>] [<a href="https://doi.org/10.1212/01.wnl.0000044049.99690.ad" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12552057">Nardocci et al. (2003)</a> identified a homozygous 595C-G transversion in exon 5 of the GCH1 gene, resulting in a pro199-to-ala (P199A) substitution. One girl also had prolonged generalized dystonic spasms, with opisthotonus, hyperextension of lower limbs, and hyperpronation of the arms, also with diurnal fluctuation. Cognitive development was normal. Laboratory results were normal and neither had hyperphenylalaninemia. Treatment with L-DOPA resulted in marked clinical improvement, and both had almost normal neurologic examination at age 15, except for slight hyperreflexia and low-normal IQ. Neither parent had any signs or symptoms suggesting a GCH1 deficiency, Patient fibroblast GCH1 activity was 8 to 9% of control values. <a href="#23" class="mim-tip-reference" title="Nardocci, N., Zorzi, G., Blau, N., Alvarez, E. F., Sesta, M., Angelini, L., Pannacci, M., Invernizzi, F., Garavaglia, B. <strong>Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency.</strong> Neurology 60: 335-337, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12552057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12552057</a>] [<a href="https://doi.org/10.1212/01.wnl.0000044049.99690.ad" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12552057">Nardocci et al. (2003)</a> interpreted the findings as expanding the clinical phenotype associated with recessive GCH1 mutations to include patients with neonatal onset of a movement disorder without hyperphenylalaninemia (see <a href="/entry/233910">233910</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12552057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro functional expression studies in yeast, <a href="#7" class="mim-tip-reference" title="Garavaglia, B., Invernizzi, F., Agostoni Carbone, M. L., Viscardi, V., Saracino, F., Ghezzi, D., Zeviani, M., Zorzi, G., Nardocci, N. <strong>GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations.</strong> J. Inherit. Metab. Dis. 27: 455-463, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15303002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15303002</a>] [<a href="https://doi.org/10.1023/B:BOLI.0000037349.08483.96" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15303002">Garavaglia et al. (2004)</a> found that the P199A mutant enzyme showed reduced activity that was further decreased at higher temperatures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15303002" 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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Cronin, S. J. F., Seehus, C., Weidinger, A., Talbot, S., Reissig, S., Seifert, M., Pierson, Y., McNeill, E., Longhi, M. S., Turnes, B. L., Kreslavsky, T., Kogler, M., and 29 others.
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Garavaglia, B., Invernizzi, F., Agostoni Carbone, M. L., Viscardi, V., Saracino, F., Ghezzi, D., Zeviani, M., Zorzi, G., Nardocci, N.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15303002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15303002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15303002" 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/10.1023/B:BOLI.0000037349.08483.96" target="_blank">Full Text</a>]
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Hagenah, J., Saunders-Pullman, R., Hedrich, K., Kabakci, K., Habermann, K., Wiegers, K., Mohrmann, K., Lohnau, T., Raymond, D., Vieregge, P., Nygaard, T., Ozelius, L. J., Bressman, S. B., Klein, C.
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[<a href="https://doi.org/10.1212/01.WNL.0000152839.50258.A2" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177267</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9177267" 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/10.1006/bbrc.1997.6632" target="_blank">Full Text</a>]
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<strong>A novel nonsense mutation of the GTP cyclohydrolase I gene in a family with dopa-responsive dystonia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359069" 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/10.1159/000053355" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11026444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11026444</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11026444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hwu, W.-L., Lu, M.-Y., Hwa, K.-Y., Fan, S.-W., Lee, Y.-M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174023</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15174023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20122" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390051093" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.270.17.10062" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s100480050025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000044049.99690.ad" target="_blank">Full Text</a>]
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Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., Nagatsu, T.
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<strong>Multiple mRNA forms of human GTP cyclohydrolase I.</strong>
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Biochem. Biophys. Res. Commun. 187: 359-365, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1520321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1520321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1520321" 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/s0006-291x(05)81501-3" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Weber1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weber, Y., Steinberger, D., Deuschl, G., Benecke, R., Muller, U.
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<strong>Two previously unrecognized splicing mutations of GCH1 in dopa-responsive dystonia: exon skipping and one base insertion.</strong>
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Neurogenetics 1: 125-127, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100480050018" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Witter1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Witter, K., Werner, T., Blusch, J. H., Schneider, E.-M., Riess, O., Ziegler, I., Rodl, W., Bacher, A., Gutlich, M.
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<strong>Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I.</strong>
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Gene 171: 285-290, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666288</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8666288" 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/10.1016/0378-1119(95)00886-1" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/25/2019
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/10/2009<br>Cassandra L. Kniffin - updated : 2/27/2007<br>Cassandra L. Kniffin - updated : 11/21/2006<br>Cassandra L. Kniffin - updated : 4/27/2005<br>Cassandra L. Kniffin - updated : 12/10/2004<br>Cassandra L. Kniffin - updated : 6/28/2004<br>Cassandra L. Kniffin - reorganized : 12/30/2003<br>Cassandra L. Kniffin - updated : 12/24/2003<br>Cassandra L. Kniffin - updated : 12/27/2002<br>Cassandra L. Kniffin - updated : 7/8/2002<br>Cassandra L. Kniffin - updated : 6/12/2002<br>Ada Hamosh - updated : 9/4/2001<br>Victor A. McKusick - updated : 8/20/2001<br>Victor A. McKusick - updated : 1/6/2000<br>Victor A. McKusick - updated : 12/13/1999<br>Victor A. McKusick - updated : 10/28/1999<br>Victor A. McKusick - updated : 10/16/1999<br>Victor A. McKusick - updated : 7/14/1999<br>Victor A. McKusick - updated : 6/17/1999<br>Orest Hurko - updated : 4/7/1999<br>Victor A. McKusick - updated : 10/8/1998<br>Victor A. McKusick - updated : 5/12/1998<br>Victor A. McKusick - updated : 5/5/1998<br>Alan F. Scott - updated : 6/26/1995
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/7/1994
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/02/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/25/2019<br>carol : 11/01/2017<br>carol : 10/31/2017<br>joanna : 08/04/2016<br>carol : 01/05/2010<br>carol : 12/17/2009<br>carol : 4/16/2009<br>carol : 4/15/2009<br>ckniffin : 4/10/2009<br>wwang : 3/5/2007<br>ckniffin : 2/28/2007<br>ckniffin : 2/27/2007<br>wwang : 12/7/2006<br>ckniffin : 11/21/2006<br>wwang : 10/19/2006<br>wwang : 5/3/2005<br>ckniffin : 4/27/2005<br>tkritzer : 12/15/2004<br>ckniffin : 12/10/2004<br>tkritzer : 6/30/2004<br>ckniffin : 6/28/2004<br>carol : 12/30/2003<br>ckniffin : 12/24/2003<br>cwells : 1/7/2003<br>ckniffin : 12/27/2002<br>tkritzer : 8/9/2002<br>ckniffin : 7/8/2002<br>carol : 6/12/2002<br>cwells : 9/14/2001<br>cwells : 9/4/2001<br>mcapotos : 8/20/2001<br>terry : 2/28/2000<br>mgross : 1/12/2000<br>mgross : 1/12/2000<br>terry : 1/6/2000<br>carol : 12/14/1999<br>terry : 12/13/1999<br>mgross : 10/28/1999<br>carol : 10/16/1999<br>jlewis : 7/30/1999<br>terry : 7/14/1999<br>jlewis : 6/23/1999<br>terry : 6/17/1999<br>carol : 4/21/1999<br>mgross : 4/12/1999<br>mgross : 4/8/1999<br>mgross : 4/7/1999<br>carol : 10/14/1998<br>terry : 10/8/1998<br>carol : 5/22/1998<br>carol : 5/12/1998<br>carol : 5/12/1998<br>terry : 5/5/1998<br>terry : 11/14/1997<br>terry : 11/11/1997<br>joanna : 11/3/1997<br>alopez : 6/13/1997<br>mark : 10/23/1996<br>terry : 10/7/1996<br>mark : 4/17/1996<br>terry : 4/10/1996<br>mimadm : 9/23/1995<br>terry : 4/14/1995<br>carol : 12/7/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600225
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GTP CYCLOHYDROLASE I; GCH1
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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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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GCH1</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230332007, 23447005, 715768000;
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</span>
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<strong>
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<em>
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Cytogenetic location: 14q22.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:54,842,017-54,902,826 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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14q22.2
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</span>
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<td>
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<span class="mim-font">
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Dystonia, DOPA-responsive
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</span>
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</td>
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<td>
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<span class="mim-font">
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128230
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</span>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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Hyperphenylalaninemia, BH4-deficient, B
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</span>
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</td>
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<td>
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<span class="mim-font">
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233910
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>GTP cyclohydrolase I (EC 3.5.4.16) catalyzes the conversion of GTP to D-erythro-7,8-dihydroneopterin triphosphate, the first and rate-limiting step in tetrahydrobiopterin (BH4) biosynthesis. Tetrahydrobiopterin is an essential cofactor for 3 aromatic amino acid monooxygenases: phenylalanine, tyrosine, and tryptophan hydroxylases. Animals can synthesize tetrahydrobiopterin in vivo from GTP through several enzymatic reactions.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening a human liver cDNA library, Togari et al. (1992) isolated 3 cDNAs corresponding to the GCH1 gene. All 3 cDNAs were identical in their central and 5-prime regions, but diverged at their 3-prime regions. Togari et al. (1992) concluded that, in humans, there are at least 3 distinct GCH1 mRNAs. Gutlich et al. (1994) determined that only the longest of the 3 cDNAs encodes an active enzyme of 250 amino acids. Proteins corresponding to the other 2 shorter cDNAs did not have enzymatic activity. By Northern blot analysis, Gutlich et al. (1994) detected a 3.6-kb mRNA in human tissues. </p><p>Ichinose et al. (1995) cloned both the human and mouse genes for GCH1, and determined that alternative use of the splice acceptor site in exon 6 is responsible for the observed heterogeneity of GCH1 mRNAs. </p><p>Witter et al. (1996) identified a genomic clone containing the 5-prime regulatory region of the GCH1 gene. The transcription start point was mapped by 5-prime RACE. The 2.6-kb region upstream from the transcription start point showed promoter activity when ligated upstream from a reporter gene. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ichinose et al. (1995) determined that both the mouse and human GCH1 genes contain 6 exons. </p><p>Bandmann et al. (1996) characterized the exon-intron boundaries of the GCH1 gene (which they symbolized GTPCH). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using somatic cell hybrids, Ichinose et al. (1994) assigned the human GCH1 gene to chromosome 14. They regionalized the gene to 14q22.1-q22.2 by fluorescence in situ hybridization. Thony et al. (1995) also mapped GCH1 to 14q21-q22 by in situ hybridization. </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>Hwu et al. (2004) found that a subset of HeLa cells expressing the GCH gly201-to-glu mutation (G201E; 600225.0004) retained expression of the GCH protein, suggesting that they were resistant to the dominant-negative effect. Differential display showed that the resistant cells had a higher expression of the molecular chaperone Hsc70 (600816). Cotransfection of Hsp40 (604572) and Hsp70 (see 140550) with G201E-containing HeLa cells resulted in higher expression of the mutant GCH protein compared to mutant cells without Hsp40 and Hsp70, although the protein had no activity. Expression of the chaperone protein Hsp90 (see 140571) in both wildtype and mutant cells stabilized the GCH protein and increased protein synthesis without increasing GCH mRNA. Hwu et al. (2004) concluded that molecular chaperones regulate GCH at the protein level, that Hsp90 may assist GCH conformation and stability, and that these molecular chaperones may be modifier genes that underlie the variable phenotypic expression in dopa-responsive dystonia (128230). </p><p>Cronin et al. (2018) found that genetic inactivation of GCH1 and inhibition of sepiapterin reductase (SPR; 182125), the terminal enzyme in the tetrahydrobiopterin (BH4) synthesis pathway, severely impaired the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogated T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augmented responses by CD4- and CD8-expressing T cells, increasing their antitumor activity in vivo. Administration of BH4 to mice markedly reduced tumor growth and expanded the population of intratumoral effector T cells. Kynurenine, a tryptophan metabolite that blocks antitumor immunity, inhibited T cell proliferation in a manner that could be rescued by BH4. Finally, Cronin et al. (2018) reported the development of a potent SPR antagonist for possible clinical use. Their data uncovered GCH1, SPR, and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity. </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>Autosomal Dominant Dopa-Responsive Dystonia</em></strong></p><p>
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|
In affected members of 4 families with autosomal dominant dopa-responsive dystonia (DRD) (DYT5; 128230), Ichinose et al. (1994) identified 4 heterozygous mutations in the GCH1 gene (600225.0001-600225.0004). </p><p>Among 36 cases of dopamine-responsive dystonia, including 33 cases from 9 British families and 3 sporadic cases, Bandmann et al. (1996) identified 6 novel mutations in the GCH1 gene, all of which were point mutations. In 4 families and 2 sporadic cases, no mutations were identified, suggesting genetic heterogeneity. </p><p>Skrygan et al. (2001) identified 4 different mutations in the GCH1 gene (see, e.g., 600225.0019) in 6 of 33 families with dopa-responsive dystonia. </p><p>Hagenah et al. (2005) identified mutations in the GCH1 gene in 20 (87%) of 23 unrelated individuals with dopa-responsive dystonia. Two patients had large deletions of more than 1 exon, which were detected only by quantitative PCR testing. Hagenah et al. (2005) stated that 85 different mutations had been reported in the GCH1 gene. </p><p>Steinberger et al. (2007) used multiple ligation-dependent probe amplification (MLPA) to examine exons 1, 2, 3, 5, and 6 of the GCH1 gene in affected members of 3 unrelated families with DRD who did not have single basepair changes. The authors identified 3 different large heterozygous GCH1 deletions, including deletion of the entire gene (600225.0021). The findings demonstrated that DRD is most likely due to haploinsufficiency of the GCH1 gene, rather than a dominant-negative effect. All patients showed characteristic signs and symptoms of DRD. </p><p><strong><em>BH4-Deficient Hyperphenylalaninemia B</em></strong></p><p>
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|
In a male infant with GCH1 deficiency manifest as hyperphenylalaninemia (HPABH4B; 233910), Blau et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0017). In another patient with GCH1 deficiency, Ichinose et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0020). </p><p><strong><em>Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia</em></strong></p><p>
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|
Furukawa et al. (1998), Hwu et al. (1999), and Nardocci et al. (2003) identified homozygous or compound heterozygous mutations in patients with dopa-responsive dystonia with or without hyperphenylalaninemia (see, e.g., 600225.0010, 600225.0016, and 600225.0022). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>There is a 4:1 female predominance in dopa-responsive dystonia. Ichinose et al. (1994) found higher GTP cyclohydrolase I activities in males than in females, a possible explanation for the difference in frequency of the disorder. The diurnal fluctuations that are characteristic of this disorder may be explained by the relatively short half-life of BH4. Patients with heterozygous mutations in the GCH1 gene may synthesize BH4 at a low rate that is not high enough to compensate for the consumption of the cofactor during the day, thus leading to aggravation of symptoms toward evening. </p><p>Hirano et al. (1997) studied a mutation in the GCH1 gene suggesting that the abnormal polypeptide encoded by mutant RNA interacts with wildtype polypeptides, generating nonfunctional heteromultimers. They suggested that more frequent occurrence of DYT5 in females than in males may be explained by the higher basal levels of the enzyme in males. </p><p>In patients with dopa-responsive dystonia, Muller et al. (1998) tabulated 29 separate mutations in the GCH1 gene. Most of the mutations resulted in truncation of the enzyme, due to the introduction of a stop codon, a frameshift mutation, or abnormal splicing. Patients who were heterozygous for GCH1 mutations developed dopa-responsive dystonia, whereas individuals who were homozygous or compound heterozygous for GCH1 mutations developed hyperphenylalaninemia with accompanying deficiency of dopamine and serotonin. The authors concluded that autosomal dominant dopa-responsive dystonia is not likely to be simply a matter of haploinsufficiency of the enzyme, because patients with DYT5 have enzyme levels that are approximately 20% of normal rather than the expected 50%. </p><p>Tamaru et al. (1998) studied the GCH1 gene and the clinical features of 8 patients from 6 families with hereditary progressive dystonia with pronounced diurnal fluctuation/dopa-responsive dystonia. Three independent GCH1 mutations were found in 3 patients. One of the patients and her asymptomatic mother were heterozygous for a novel mutation at the initiation codon. The 3 patients with dissimilar GCH1 mutations showed similar clinical features, including isolated limb dystonia progressing to generalized dystonia, diurnal fluctuation of symptoms, and favorable response to levodopa. The other 5 patients with normal sequences in the GCH1 gene presented several features not manifested by the 3 patients with the mutations. </p><p>In affected members of a Japanese family with hereditary progressive dystonia with marked diurnal fluctuation, but no mutation in the coding region or splice junctions of the GCH1 gene, Inagaki et al. (1999) quantified the mRNA levels of GCH1 in phytohemagglutinin-stimulated mononuclear blood cells. They found that the amounts of GCH1 mRNA were decreased to about 40% of the normal level in both patients and carriers. In addition, they found that the GCH1 mRNA was transcribed from only 1 allele, indicating that the other allele was in an inactive state. These results suggested that some novel mutations exist on 1 of the alleles in an unknown region of the GCH1 gene and may decrease the GCH1 mRNA, causing the manifestations of the disorder. </p><p>Among 58 patients with dopa-responsive dystonia, Steinberger et al. (2000) identified mutations in the GCH1 gene in 30 individuals from 22 families. Thirteen of the mutations were familial, 3 occurred de novo, and inheritance could not be determined in 6 cases. Four novel mutations were identified, including a missense mutation, a frameshift mutation, and 2 intronic mutations that affected donor splice sites. Since there was no difference in therapeutic doses of L-DOPA between patients with or without a GCH1 mutation, the authors suggested that the phenotype may be caused by other genes involved in the synthesis of dopamine. </p><p>Among 168 Caucasian adults, Tegeder et al. (2006) found that a GCH1 haplotype (allelic frequency of 15%) causing decreased enzyme levels was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and stimulated immortalized leukocytes from haplotype carriers showed decreased upregulation of GCH1 compared to controls. Based on these findings and rodent models, Tegeder et al. (2006) concluded that alterations in the concentration of BH4 due to GCH1 activity modify pain sensitivity and susceptibility. </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>The Hph1 mouse exhibits hyperphenylalaninemia and a reduction in GTP cyclohydrolase I activity (McDonald et al., 1988). Bode et al. (1988) showed that the Hph1 gene in the mouse is tightly linked to the nucleoside phosphorylase gene (PNP; 164050) on chromosome 14. This region shows syntenic homology with the region of human chromosome 14 containing the GCH1 and PNP genes. Ichinose et al. (1995) mapped the mouse Gch gene to region C2-C3 of chromosome 14 by in situ hybridization. Montanez and McDonald (1999) demonstrated linkage between the hph1 mutation and the Gch locus on mouse chromosome 14, supporting the use of the hph1 mouse mutant as a bona fide model system for the human disorder of GTP cyclohydrolase I deficiency. </p><p>Hyland et al. (2003) found that hph1 mice have low brain levels of BH4, catecholamines, serotonin, and their metabolites, together with low levels of tyrosine hydroxylase protein within the striatum. These findings are similar to the neurochemical findings in human patients with mutations in the GCH1 gene, suggesting that the hph1 mouse is a good model system of GCH1 deficiency. </p><p>In rodent models of neuropathic and inflammatory pain, Tegeder et al. (2006) found an increase of BH4 resulting from upregulation or enhanced enzyme activity of Gch1. Inhibition of BH4 synthesis by blocking Gch1 activity resulted in attenuation of the pain and prevented nerve injury-evoked excess nitric oxide production, whereas administration of BH4 exacerbated pain. </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>22 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 DYSTONIA, DOPA-RESPONSIVE</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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GCH1, ARG88TRP
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<br />
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SNP: rs104894433,
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gnomAD: rs104894433,
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ClinVar: RCV000009853
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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 family with progressive dystonia with diurnal variation (128230), also known as dopa-responsive dystonia, Ichinose et al. (1994) identified a heterozygous C-T transition in the GCH1 gene, resulting in an arg88-to-trp substitution (R88W). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 DYSTONIA, DOPA-RESPONSIVE</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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GCH1, ASP134VAL
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<br />
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SNP: rs104894437,
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ClinVar: RCV000009854
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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 affected members of a family with progressive dystonia with diurnal variation (128230), Ichinose et al. (1994) identified a heterozygous A-T transversion in the GCH1 gene, resulting in an asp134-to-val (D134V) substitution of valine. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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GCH1, 2-BP INS
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<br />
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SNP: rs2140127822,
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ClinVar: RCV000009855
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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 affected members of a family with progressive dystonia with marked diurnal fluctuation (128230), Ichinose et al. (1994) identified a heterozygous 2-bp insertion in the GCH1 gene, leading to a frameshift and a premature stop codon at position 197. </p>
|
|
</span>
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</div>
|
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<div>
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|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
GCH1, GLY201GLU
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<br />
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|
|
SNP: rs104894438,
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|
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ClinVar: RCV000009856
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with progressive dystonia with diurnal variation (128230), Ichinose et al. (1994) identified a heterozygous G-A transition in the GCH1 gene, resulting in a gly201-to-glu (G201E) substitution. </p><p>In vitro, Hwu et al. (2000) found that expression of the G201E mutation resulted in rapid degradation of the GCH1 protein with approximately 5% enzyme activity. Cotransfection studies showed that the G201E mutation interacted with the wildtype protein, decreasing its level and activity. Hwu et al. (2000) concluded that the G201E mutation exerts a dominant-negative effect, either by inhibition or destabilization. Similar studies with R249S (600225.0016) showed no dominant-negative effect, consistent with a recessive dopa-responsive dystonia mutation. </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>.0005 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
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|
|
|
GCH1, IVS1, A-G, -2
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|
|
|
<br />
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|
|
|
SNP: rs2140074226,
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|
|
ClinVar: RCV000009857
|
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|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with dopa-responsive dystonia (128230), Weber et al. (1997) identified 2 previously unrecognized splice site mutations of GCH1 which affected consensus splice acceptor (AG) sites. The first mutation was an A-G transition at position -2 of intron 1 of GCH1, predicted to result in the skipping of exon 2. Fusion of exons 1 and 3 caused a frameshift that generated a premature stop codon. The second mutation was an A-G transition at position -2 of intron 2 (600225.0006), predicted to generated a new splice acceptor site 1 basepair upstream of the wildtype splice site. This, together with a pyrimidine stretch upstream of the new splice site, rendered this site functional and generated a transcript with the insertion of 1 base, i.e., the G of the wildtype splice site. This in turn caused a frameshift, including the introduction of a premature stop codon. Both mutations generated truncated GTP cyclohydrolase polypeptides. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, IVS2, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2039866854,
|
|
|
|
|
|
|
|
ClinVar: RCV001091044, RCV001824413
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 600225.0005 and Weber et al. (1997). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, MET1ILE
|
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|
|
|
<br />
|
|
|
|
SNP: rs104894439,
|
|
|
|
|
|
|
|
ClinVar: RCV000009859
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 36-year-old woman with DYT5 (128230) and her asymptomatic mother, Tamaru et al. (1998) found heterozygosity for a G-C transversion in the initiation codon of the GCH1 gene, causing a met1-to-ile (M1I) substitution. The mutation abolished the first AUG codon. The next AUG codon lies at the position corresponding to amino acid 20, resulting in a frameshift and a UGA termination codon located 139 nucleotides downstream. The putative translation product was a 46-amino acid peptide completely different from the normal GCH1 gene product. The patient had had intermittent internal rotation of her legs, particularly the left, since the age of 8. The symptoms were aggravated toward evening and gradually spread to the other limbs. Postural tremor became apparent after the age of 20. During her thirties, she could walk for 1 hour in the morning, becoming immobile toward evening. At examination at the age of 35, both feet tended to turn inward and plantarflex. She walked with her left foot circumflexed. Small doses of levodopa provided a considerable and sustained improvement. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, HIS144PRO
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<br />
|
|
|
|
SNP: rs104894440,
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|
|
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|
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|
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ClinVar: RCV000009860
|
|
|
|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old woman with DYT5 (128230) and her asymptomatic father, Tamaru et al. (1998) found heterozygosity for a his144-to-pro (H144P) missense mutation of the GCH1 gene. The patient had developed knee disturbances at the age of 7 due to pes equinovarus of both legs, dominantly in the left one. Her head turned involuntarily to the right, which worsened in the afternoon. When she was 18 years old, she noted clumsiness of the hands due to postural tremor. Her symptoms were completely controlled after she started levodopa therapy. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
GCH1, IVS2, G-C, +1
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<br />
|
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|
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SNP: rs2140073990,
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|
|
ClinVar: RCV000009861, RCV001851775
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 23-year-old man with DYT5 (128230) and his asymptomatic mother, Tamaru et al. (1998) found heterozygosity for a G-C transversion at the 5-prime end of intron 2 of GCH1, causing the skipping of exon 1 to exon 3. The man had first noticed flexion-inversion of the right foot, especially in the afternoon, at the age of 10 years. His dystonia gradually progressed to involve all limbs within 5 years, but was more pronounced in the lower limbs. At the age of 22 years, he showed pronounced dystonic posturing in the left hand and leg as well as scoliosis. He walked on his toes with torticollis to the left and carried his left arm in the flexed position. After the initiation of levodopa therapy, his symptoms improved remarkably. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, 1-BP DEL, 351A
|
|
|
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|
|
<br />
|
|
|
|
SNP: rs2140074192,
|
|
|
|
|
|
|
|
ClinVar: RCV002508111
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
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<span class="mim-text-font">
|
|
<p>In a 6-year-old girl with dopa-responsive dystonia (see 233910), Furukawa et al. (1998) identified a 1-bp deletion in exon 2 of the GCH1 gene. Her mother, maternal grandmother, and great-grandmother, all of whom had progressive dystonia with diurnal variation, also carried the same deletion. Only the proband with motor delay was a compound heterozygote for an additional mutation, a T-C transition in exon 6, resulting in a met221-to-thr substitution (600225.0011), which she had inherited from her asymptomatic father. The proband responded to treatment with tetrahydrobiopterin and levodopa. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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|
|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
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<span class="mim-text-font">
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GCH1, MET221THR
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|
<br />
|
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|
|
SNP: rs104894434,
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|
|
|
gnomAD: rs104894434,
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ClinVar: RCV001260617, RCV001851776, RCV002223756, RCV002508112, RCV004766995, RCV004786251
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>See 600225.0010 and Furukawa et al. (1998). </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, GLY108ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894435,
|
|
|
|
|
|
|
|
ClinVar: RCV000634833, RCV001659690, RCV002508113
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 17-year-old male with dopa-responsive dystonia (see 233910) Furukawa et al. (1998) identified a novel G-A transition in exon 1 of the GCH1 gene, resulting in a gly108-to-asp (G108D) substitution, which was inherited from his asymptomatic father, who was not examined. The patient was a compound heterozygote for an additional mutation in the GCH1 gene, an A-G transition in exon 6, resulting in a lys224-to-arg (K224R) substitution (600225.0013), which he had inherited from his asymptomatic mother. The boy could not walk until age 4, at which time language was normal except for mild dysarthria. Between the ages of 4 and 6 years, the patient's previously acquired motor and speech functions deteriorated, and he subsequently became wheelchair bound and mute. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, LYS224ARG
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs41298442,
|
|
|
|
|
|
gnomAD: rs41298442,
|
|
|
|
|
|
ClinVar: RCV000009865, RCV000517539, RCV000525589, RCV000989227, RCV002255090, RCV002508114, RCV002512951, RCV005003351
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 600225.0012 and Furukawa et al. (1998). </p><p>Leuzzi et al. (2002) reported a consanguineous Italian family in which 5 members over 3 generations were affected with variable severity of dopa-responsive dystonia (128230) with features of a myoclonus-dystonia syndrome (see, e.g., 159900). The most severely affected individual was the proband, the son of first cousins, who developed progressive myoclonic jerky movements of his upper limbs, lower limbs, trunk, and face beginning at the age of 3 years. He also exhibited mild dystonic postures of the upper limbs and neck, mild bradykinesia, and lack of facial expression. Blood prolactin was elevated and CSF homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), and biopterin were reduced. Treatment with L-DOPA resulted in marked improvement. In 4 affected members who were tested, including the proband, Leuzzi et al. (2002) identified a heterozygous 671A-G missense mutation in the GCH1 gene, resulting in a lys224-to-arg (L224R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, ALA196SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894436,
|
|
|
|
|
|
gnomAD: rs104894436,
|
|
|
|
|
|
ClinVar: RCV000009867
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Steinberger et al. (1999) reported a 49-year-old male with a 3-year history of dopa-responsive dystonia (128230) manifested mainly as an oromandibular dystonia involving involuntary movements of the tongue and lips which worsened during exercise. The patient also showed subtle abnormal posturing of his right hand when he wrote with his left. The oromandibular dystonia partially responded to treatment with levodopa and benserazide. The patient's family history revealed no obvious cases of dystonia, although his father reportedly had abnormal facial movements in childhood that disappeared during adolescence. By DNA analysis, Steinberger et al. (1999) identified a novel 586G-T transversion in exon 5 of the GCH1 gene, resulting in an ala196-to-ser (A196S) substitution. They also identified a synonymous mutation, a 582G-A transition in exon 5, on the same chromosome as the presumed pathogenic mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, ILE135LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894441,
|
|
|
|
|
|
|
|
ClinVar: RCV000009868
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French family with 4 sibs affected with juvenile-onset dopa-responsive dystonia and simultaneous or later-onset parkinsonism (128230), Brique et al. (1999) found heterozygosity for an A-T transversion in exon 2 of the GCH1 gene, resulting in an ile135-to-lys (I135K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, ARG249SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894442,
|
|
|
|
|
|
gnomAD: rs104894442,
|
|
|
|
|
|
ClinVar: RCV000518763, RCV002508115
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hwu et al. (1999) described a girl with progressive dopa-responsive dystonia with diurnal fluctuation (see 233910) beginning at age 2 years and 8 months. There was no family history of the disorder. Plasma phenylalanine was normal. Genetic analysis identified a homozygous 747C-G transversion in the GCH1 gene, resulting in an arg249-to-ser (R249S) substitution. The patient's cells had low, but measurable enzyme activity, compatible with dopa-responsive dystonia. Arginine-249 is located at the C terminus of the protein, outside the catalytic site. E. coli-expressed recombinant R249S mutant protein possessed normal enzyme activity and kinetics. However, in transfected eukaryotic cells, the expression level of the R249S mutant protein was lower than that of the wildtype protein. Therefore, Hwu et al. (1999) suspected that R249S is a destabilizing mutation. Both parents were heterozygous for the mutation, and only mutant clones could be found in the patient, whereas both the mutant and wildtype forms were found in the parents. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, MET211ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894443,
|
|
|
|
|
|
|
|
ClinVar: RCV004576896
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with BH4-dependent hyperphenylalaninemia due to GCH1 deficiency (HPABH4B; 233910), Ichinose et al. (1995) and Blau et al. (1995) identified a homozygous G-to-A transition in the GCH1 gene, resulting in a met211-to-ile (M211I) substitution. In vitro functional expression studies in E. coli showed that the mutant protein lacked enzymatic activity. The patient had progressive neurologic symptoms, including hypotonia and uncoordinated movements. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, GLN48TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894444,
|
|
|
|
|
|
|
|
ClinVar: RCV000009871, RCV001390287
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Korean family with dopa-responsive dystonia (128230), Hong et al. (2001) identified a heterozygous 142C-T transition in exon 1 of the GCH1 gene, resulting in nonsense mutation (gln48-to-ter; Q48X). Two sisters and 3 of their children were affected and carried the mutation. Expression was milder in the 1 male of the 5 symptomatic relatives; 3 individuals in another branch of the family carried the mutation but were asymptomatic. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, IVS5, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555358507,
|
|
|
|
|
|
|
|
ClinVar: RCV000634835, RCV001090536, RCV001836648
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an individual with dopa-responsive dystonia (128230), Skrygan et al. (2001) identified a G-A transition at IVS5+1. Three members of the family carried the mutation, which was inherited from the father to the daughter and son, but only 1 was symptomatic. Examination of the mRNA showed an exon 5 skipping that results in reduction of the enzyme activity in cultured fibroblasts to 4 to 17% compared to controls. The son was symptomatic at the age of 3 years and was successfully treated with L-DOPA/carbidopa. After 20 years, this therapy was terminated and for the next 6 years he was free of symptoms. With increased motor activity, symptoms reappeared and the therapy was reintroduced. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, ARG184HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894445,
|
|
|
|
|
|
|
|
ClinVar: RCV000009873, RCV003137509, RCV003764543, RCV004576897
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with BH4-dependent hyperphenylalaninemia due to GTP cyclohydrolase I deficiency (233910), Ichinose et al. (1995) identified a homozygous G-A change in the GCH1 gene, resulting in an arg184-to-his (R184H) substitution. Functional expression studies showed that the mutation caused a loss of enzyme activity. She developed feeding problems, poor sucking, and poor muscle tone in the first week of life, and later showed delayed development. By the age of 2 years, the child was unable to walk and developed seizures and choreoathetosis. Urinary pterins showed a profound deficiency in neopterin and biopterin. She died at age 10 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 DYSTONIA, DOPA-RESPONSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009874
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a 2-generation family with DRD (128230), Steinberger et al. (2007) identified a heterozygous complete deletion of the GCH1 gene. The findings suggested that the phenotype results from haploinsufficiency rather than a dominant-negative effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCH1, PRO199ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852633,
|
|
|
|
|
|
|
|
ClinVar: RCV002508116
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In monozygotic twin girls with onset of extrapyramidal features in the first months of life, Nardocci et al. (2003) identified a homozygous 595C-G transversion in exon 5 of the GCH1 gene, resulting in a pro199-to-ala (P199A) substitution. One girl also had prolonged generalized dystonic spasms, with opisthotonus, hyperextension of lower limbs, and hyperpronation of the arms, also with diurnal fluctuation. Cognitive development was normal. Laboratory results were normal and neither had hyperphenylalaninemia. Treatment with L-DOPA resulted in marked clinical improvement, and both had almost normal neurologic examination at age 15, except for slight hyperreflexia and low-normal IQ. Neither parent had any signs or symptoms suggesting a GCH1 deficiency, Patient fibroblast GCH1 activity was 8 to 9% of control values. Nardocci et al. (2003) interpreted the findings as expanding the clinical phenotype associated with recessive GCH1 mutations to include patients with neonatal onset of a movement disorder without hyperphenylalaninemia (see 233910). </p><p>By in vitro functional expression studies in yeast, Garavaglia et al. (2004) found that the P199A mutant enzyme showed reduced activity that was further decreased at higher temperatures. </p>
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[PubMed: 1520321]
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[Full Text: https://doi.org/10.1016/s0006-291x(05)81501-3]
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Weber, Y., Steinberger, D., Deuschl, G., Benecke, R., Muller, U.
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<strong>Two previously unrecognized splicing mutations of GCH1 in dopa-responsive dystonia: exon skipping and one base insertion.</strong>
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Neurogenetics 1: 125-127, 1997.
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[PubMed: 10732814]
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[Full Text: https://doi.org/10.1007/s100480050018]
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Witter, K., Werner, T., Blusch, J. H., Schneider, E.-M., Riess, O., Ziegler, I., Rodl, W., Bacher, A., Gutlich, M.
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<strong>Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I.</strong>
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Gene 171: 285-290, 1996.
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[PubMed: 8666288]
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[Full Text: https://doi.org/10.1016/0378-1119(95)00886-1]
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Ada Hamosh - updated : 02/25/2019<br>Cassandra L. Kniffin - updated : 4/10/2009<br>Cassandra L. Kniffin - updated : 2/27/2007<br>Cassandra L. Kniffin - updated : 11/21/2006<br>Cassandra L. Kniffin - updated : 4/27/2005<br>Cassandra L. Kniffin - updated : 12/10/2004<br>Cassandra L. Kniffin - updated : 6/28/2004<br>Cassandra L. Kniffin - reorganized : 12/30/2003<br>Cassandra L. Kniffin - updated : 12/24/2003<br>Cassandra L. Kniffin - updated : 12/27/2002<br>Cassandra L. Kniffin - updated : 7/8/2002<br>Cassandra L. Kniffin - updated : 6/12/2002<br>Ada Hamosh - updated : 9/4/2001<br>Victor A. McKusick - updated : 8/20/2001<br>Victor A. McKusick - updated : 1/6/2000<br>Victor A. McKusick - updated : 12/13/1999<br>Victor A. McKusick - updated : 10/28/1999<br>Victor A. McKusick - updated : 10/16/1999<br>Victor A. McKusick - updated : 7/14/1999<br>Victor A. McKusick - updated : 6/17/1999<br>Orest Hurko - updated : 4/7/1999<br>Victor A. McKusick - updated : 10/8/1998<br>Victor A. McKusick - updated : 5/12/1998<br>Victor A. McKusick - updated : 5/5/1998<br>Alan F. Scott - updated : 6/26/1995
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Victor A. McKusick : 12/7/1994
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