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Entry
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- *300836 - ANOSMIN 1; ANOS1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300836</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300836">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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=ENSG00000011201;t=ENST00000262648" 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=3730" 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=300836" 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=ENSG00000011201;t=ENST00000262648" 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_000216,XM_005274501" 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_000216" 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=300836" 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://www.proteinatlas.org/search/ANOS1" 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/34025,237597,307080,1197219,119395746,119619165,134048661,187952607,187953557,530421074,906358677,2462629408" 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/P23352" 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=3730" 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=ENSG00000011201;t=ENST00000262648" 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=ANOS1" 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=ANOS1" 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+3730" 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/ANOS1" 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:3730" 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/3730" 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=chrX&hgg_gene=ENST00000262648.8&hgg_start=8528874&hgg_end=8732137&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:6211" 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:6211" 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/anos1" 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=300836[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=300836[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/ANOS1/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/ENSG00000011201" 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=ANOS1" 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=ANOS1" 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=ANOS1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ANOS1&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/PA30012" 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:6211" 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/FBgn0039155.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="http://v1.marrvel.org/search/gene/ANOS1#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="https://www.ncbi.nlm.nih.gov/gene/3730/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=3730" 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=WBGene00002181;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-000201-13" 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://reactome.org/content/query?q=ANOS1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300836
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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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ANOSMIN 1; ANOS1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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KALLMANN SYNDROME INTERVAL GENE 1; KALIG1<br />
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ADHESION MOLECULE-LIKE, X-LINKED; ADMLX<br />
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KAL1 GENE; KAL1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ANOS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ANOS1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/X/43?start=-3&limit=10&highlight=43">Xp22.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:8528874-8732137&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'})">X:8,528,874-8,732,137</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/X/43?start=-3&limit=10&highlight=43">
|
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Xp22.31
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/308700"> 308700 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/300836" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300836" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The KAL1 gene encodes a protein, anosmin, that plays a key role in the migration of GNRH (<a href="/entry/152760">152760</a>) neurons and olfactory nerves to the hypothalamus (summary by <a href="#4" class="mim-tip-reference" title="Cariboni, A., Pimpinelli, F., Colamarino, S., Zaninetti, R., Piccolella, M., Rumio, C., Piva, F., Rugarli, E. I., Maggi, R. <strong>The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons.</strong> Hum. Molec. Genet. 13: 2781-2791, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15471890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15471890</a>] [<a href="https://doi.org/10.1093/hmg/ddh309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15471890">Cariboni et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15471890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Legouis, R., Hardelin, J.-P., Levilliers, J., Claverie, J.-M., Compain, S., Wunderle, V., Millasseau, P., Le Paslier, D., Cohen, D., Caterina, D., Bougueleret, L., Delemarre-Van de Waal, H., Lutfalla, G., Weissenbach, J., Petit, C. <strong>The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.</strong> Cell 67: 423-435, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1913827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1913827</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90193-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1913827">Legouis et al. (1991)</a> sequenced 67 kb of genomic DNA within the X-linked Kallmann syndrome (<a href="/entry/308700">308700</a>) critical region. They found 2 candidate exons, identified by multiparameter computer programs, in a cDNA encoding a protein of 679 amino acids. This candidate gene, ADMLX (adhesion molecule-like, X-linked), was interrupted in its 3-prime coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. The predicted protein sequence showed homologies with the fibronectin type III (FN3) repeat. Thus, ADMLX encodes a putative adhesion molecule consistent with the defect of embryonic neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1913827" 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="#8" class="mim-tip-reference" title="Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., Brown, C. J., Willard, H. F., Lawrence, C., Persico, M. G., Camerino, G., Ballabio, A. <strong>A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.</strong> Nature 353: 529-536, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1922361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1922361</a>] [<a href="https://doi.org/10.1038/353529a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1922361">Franco et al. (1991)</a> showed that the KALIG1 gene shares homology with molecules involved in cell adhesion and axonal pathfinding, further supporting the notion that a molecular defect in this gene causes the neuronal migration defect underlying Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1922361" 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="#14" class="mim-tip-reference" title="Legouis, R., Cohen-Salmon, M., del Castillo, I., Levilliers, J., Capy, L., Mornon, J.-P., Petit, C. <strong>Characterization of the chicken and quail homologues of the human gene responsible for the X-linked Kallmann syndrome.</strong> Genomics 17: 516-518, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406507</a>] [<a href="https://doi.org/10.1006/geno.1993.1360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406507">Legouis et al. (1993)</a> determined the entire coding sequence of chicken and quail KAL cDNAs and demonstrated an overall identity of 73% and 72%, respectively, with human KAL cDNA. This corresponds to 76% and 75% identity at the protein level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8406507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="del Castillo, I., Cohen-Salmon, M., Blanchard, S., Lutfalla, G., Petit, C. <strong>Structure of the X-linked Kallmann syndrome gene and its homologous pseudogene on the Y chromosome.</strong> Nature Genet. 2: 305-310, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303284</a>] [<a href="https://doi.org/10.1038/ng1292-305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303284">Del Castillo et al. (1992)</a> demonstrated that the KAL1 gene contains 14 exons spanning 120 to 200 kb that correlate with the distribution of domains in the predicted protein including 4 fibronectin type III repeats. The homologous locus, KALP, on Yq11 has several large deletions and a number of small insertions, deletions, and base substitutions which indicate that it is a nonprocessed pseudogene. The sequence divergence between KAL1 and KALP in humans, and the chromosomal location of KAL homologous sequences in other primates, suggested that KALP and the steroid sulfatase pseudogene (see <a href="/entry/300747">300747</a>) on Yq11 were involved in the same rearrangement event on the Y chromosome during primate evolution. <a href="#13" class="mim-tip-reference" title="Incerti, B., Guioli, S., Pragliola, A., Zanaria, E., Borsani, G., Tonlorenzi, R., Bardoni, B., Franco, B., Wheeler, D., Ballabio, A., Camerino, G. <strong>Kallmann syndrome gene on the X and Y chromosomes: implications for evolutionary divergence of human sex chromosomes.</strong> Nature Genet. 2: 311-314, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303285</a>] [<a href="https://doi.org/10.1038/ng1292-311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303285">Incerti et al. (1992)</a>, who localized the KALP pseudogene to Yq11.2, came to similar conclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1303284+1303285" 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="#8" class="mim-tip-reference" title="Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., Brown, C. J., Willard, H. F., Lawrence, C., Persico, M. G., Camerino, G., Ballabio, A. <strong>A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.</strong> Nature 353: 529-536, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1922361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1922361</a>] [<a href="https://doi.org/10.1038/353529a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1922361">Franco et al. (1991)</a> mapped a gene, which they called KALIG1 (Kallmann syndrome interval gene-1), to the Kallmann syndrome critical region on chromosome Xp22.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1922361" 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="#25" class="mim-tip-reference" title="Soussi-Yanicostas, N., Hardelin, J.-P., del Mar Arroyo-Jimenez, M., Ardouin, O., Legouis, R., Levilliers, J., Traincard, F., Betton, J.-M., Cabanie, L., Petit, C. <strong>Initial characterization of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system.</strong> J. Cell Sci. 109: 1749-1757, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8832397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8832397</a>] [<a href="https://doi.org/10.1242/jcs.109.7.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8832397">Soussi-Yanicostas et al. (1996)</a> showed that the KAL protein is N-glycosylated, secreted in the cell culture medium, and localized at the cell surface. Upon transfection of Chinese hamster ovary (CHO) cells with human KAL cDNA, the corresponding encoded protein was produced. Several lines of evidence indicated that heparan-sulfate chains of proteoglycan(s) are involved in the binding of the KAL protein to the cell membrane. The authors generated polyclonal and monoclonal antibodies to the purified KAL protein. With these, they detected and characterized the protein encoded by the KAL gene in the chicken central nervous system at late stages of embryonic development. The protein is synthesized by definite neuronal cell populations, including Purkinje cells in the cerebellum, mitral cells in the olfactory bulbs, and several subpopulations in the optic tectum, and the striatum. The protein, with an approximate molecular mass of 100 kD, was named anosmin-1 by the authors in reference to the deficiency of the sense of smell that characterizes Kallmann disease. Anosmin-1 was thought to be an extracellular matrix component. Since heparin treatment of cell membrane fractions from cerebellum and tectum resulted in the release of the protein, <a href="#25" class="mim-tip-reference" title="Soussi-Yanicostas, N., Hardelin, J.-P., del Mar Arroyo-Jimenez, M., Ardouin, O., Legouis, R., Levilliers, J., Traincard, F., Betton, J.-M., Cabanie, L., Petit, C. <strong>Initial characterization of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system.</strong> J. Cell Sci. 109: 1749-1757, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8832397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8832397</a>] [<a href="https://doi.org/10.1242/jcs.109.7.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8832397">Soussi-Yanicostas et al. (1996)</a> suggested that 1 or several heparan-sulfate proteoglycans are involved in the binding of anosmin-1 to the membranes in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8832397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Rugarli, E. I., Ghezzi, C., Valsecchi, V., Ballabio, A. <strong>The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component.</strong> Hum. Molec. Genet. 5: 1109-1115, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842728</a>] [<a href="https://doi.org/10.1093/hmg/5.8.1109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8842728">Rugarli et al. (1996)</a> reported that KAL encodes a predicted 680-amino acid polypeptide with a protease inhibitor domain that is followed by 4 fibronectin type III repeats. Because the low abundance of this protein hampered biochemical characterization, they carried out transfection experiments to overexpress human and chick KAL in eukaryotic cells. <a href="#21" class="mim-tip-reference" title="Rugarli, E. I., Ghezzi, C., Valsecchi, V., Ballabio, A. <strong>The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component.</strong> Hum. Molec. Genet. 5: 1109-1115, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842728</a>] [<a href="https://doi.org/10.1093/hmg/5.8.1109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8842728">Rugarli et al. (1996)</a> reported that KAL is localized on the cell surface and it appears to be secreted as a diffusible molecule. They demonstrated that KAL undergoes proteolytic cleavage to yield a diffusible component and that this diffusible form is incorporated into the extracellular matrix. <a href="#21" class="mim-tip-reference" title="Rugarli, E. I., Ghezzi, C., Valsecchi, V., Ballabio, A. <strong>The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component.</strong> Hum. Molec. Genet. 5: 1109-1115, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842728</a>] [<a href="https://doi.org/10.1093/hmg/5.8.1109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8842728">Rugarli et al. (1996)</a> postulated that once incorporated into the extracellular matrix of the olfactory bulb, KAL might promote the ultimate migration and target recognition of olfactory axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8842728" 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="Soussi-Yanicostas, N., de Castro, F., Julliard, A. K., Perfettini, I., Chedotal, A., Petit, C. <strong>Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons.</strong> Cell 109: 217-228, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007408</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00713-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007408">Soussi-Yanicostas et al. (2002)</a> showed that anti-anosmin-1 antibodies blocked the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhanced axonal branching of these dissociated neurons in culture. Coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrated that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. The authors concluded that anosmin-1 has a dual branch-promoting and guidance activity and is involved in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bulow, H. E., Berry, K. L., Topper, L. H., Peles, E., Hobert, O. <strong>Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.</strong> Proc. Nat. Acad. Sci. 99: 6346-6351, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11983919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11983919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11983919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.092128099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11983919">Bulow et al. (2002)</a> showed that expression of the C. elegans homolog of KAL1 in selected sensory and interneuron classes caused a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans Kal1 expression caused a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities required different domains of the KAL1 protein. In a genetic modifier screen, <a href="#3" class="mim-tip-reference" title="Bulow, H. E., Berry, K. L., Topper, L. H., Peles, E., Hobert, O. <strong>Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.</strong> Proc. Nat. Acad. Sci. 99: 6346-6351, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11983919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11983919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11983919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.092128099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11983919">Bulow et al. (2002)</a> isolated several loci that either suppressed or enhanced the Kal1-induced axonal defects, 1 of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan 6-O-sulfotransferase (<a href="/entry/604846">604846</a>). <a href="#3" class="mim-tip-reference" title="Bulow, H. E., Berry, K. L., Topper, L. H., Peles, E., Hobert, O. <strong>Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.</strong> Proc. Nat. Acad. Sci. 99: 6346-6351, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11983919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11983919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11983919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.092128099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11983919">Bulow et al. (2002)</a> hypothesized that KAL1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11983919" 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>Based on their finding that loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1; <a href="/entry/136350">136350</a>) cause an autosomal form of hypogonadotropic hypogonadism with anosmia (HH2; Kallmann syndrome, <a href="/entry/147950">147950</a>), <a href="#6" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> proposed that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling, that there is an interaction between anosmin-1 and FGFR1, and that the higher prevalence of the disease in males is due to gender difference in anosmin-1 dosage, because KAL1 partially escapes X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cariboni, A., Pimpinelli, F., Colamarino, S., Zaninetti, R., Piccolella, M., Rumio, C., Piva, F., Rugarli, E. I., Maggi, R. <strong>The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons.</strong> Hum. Molec. Genet. 13: 2781-2791, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15471890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15471890</a>] [<a href="https://doi.org/10.1093/hmg/ddh309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15471890">Cariboni et al. (2004)</a> showed a direct action of anosmin-1 on the migratory activity of GNRH (<a href="/entry/152760">152760</a>) neurons. They found that exposing immortalized migrating GnRH neurons to anosmin-1-enriched media produced a cell-specific chemotactic response. Mutant anosmin-1 (<a href="/entry/308700#0007">308700.0007</a>)-enriched media did not affect the chemomigration of GnRH neurons. Anosmin bound to the cell surface of neurons by interacting with the heparan sulfate proteoglycans, and the chemotactic effect of anosmin-1-enriched media could be specifically blocked by heparin or by heparitinase pretreatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15471890" 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="#17" class="mim-tip-reference" title="Maya-Nunez, G., Cuevas-Covarrubias, S., Zenteno, J. C., Ulloa-Aguirre, A., Kofman-Alfaro, S., Mendez, J. P. <strong>Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene.</strong> Clin. Endocr. 48: 713-718, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9713559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9713559</a>] [<a href="https://doi.org/10.1046/j.1365-2265.1998.00406.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9713559">Maya-Nunez et al. (1998)</a> described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (STS; <a href="/entry/300747">300747</a>). The 20-year-old subject had hypogonadism and anosmia, as well as generalized ichthyosis (see <a href="/entry/308100">308100</a>). They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9713559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient and his brother with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#2" class="mim-tip-reference" title="Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A. <strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong> New Eng. J. Med. 326: 1752-1755, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>] [<a href="https://doi.org/10.1056/NEJM199206253262606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1594017">Bick et al. (1992)</a> detected a 3,300-bp deletion in the KAL1 gene (<a href="#0001">300836.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1594017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., Petit, C. <strong>Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.</strong> Hum. Molec. Genet. 2: 373-377, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8504298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8504298</a>] [<a href="https://doi.org/10.1093/hmg/2.4.373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8504298">Hardelin et al. (1993)</a> reported results of a mutation search of the KAL1 gene in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann syndrome patients; 6 of 11 males with identified alterations of the KAL gene showed this feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8504298" 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="#20" class="mim-tip-reference" title="Parenti, G., Rizzolo, M. G., Ghezzi, M., Di Maio, S., Sperandeo, M. P., Incerti, B., Franco, B., Ballabio, A., Andria, G. <strong>Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene.</strong> Am. J. Med. Genet. 57: 476-478, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677154</a>] [<a href="https://doi.org/10.1002/ajmg.1320570323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7677154">Parenti et al. (1995)</a> reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposmia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677154" 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="Georgopoulos, N. A., Pralong, F. P., Seidman, C. E., Seidman, J. G., Crowley, W. F., Jr., Vallejo, M. <strong>Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.</strong> J. Clin. Endocr. Metab. 82: 213-217, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8989261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8989261</a>] [<a href="https://doi.org/10.1210/jcem.82.1.3692" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8989261">Georgopoulos et al. (1997)</a> determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency, a heritable condition characterized by a functional deficit in GNRH secretion. Only 1 of 21 (5%) of these patients had a KAL1 mutation (a deletion of 14 bases starting at codon 464); this patient also had anosmia (Kallmann syndrome). In each of 3 unrelated patients from families with an X-linked mode of inheritance, 3 different mutations were detected. These were a single-base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution, and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. <a href="#9" class="mim-tip-reference" title="Georgopoulos, N. A., Pralong, F. P., Seidman, C. E., Seidman, J. G., Crowley, W. F., Jr., Vallejo, M. <strong>Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.</strong> J. Clin. Endocr. Metab. 82: 213-217, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8989261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8989261</a>] [<a href="https://doi.org/10.1210/jcem.82.1.3692" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8989261">Georgopoulos et al. (1997)</a> suggested that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8989261" 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="Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., Jr., Vallejo, M. <strong>The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.</strong> J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297579</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297579">Oliveira et al. (2001)</a> examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). <a href="#19" class="mim-tip-reference" title="Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., Jr., Vallejo, M. <strong>The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.</strong> J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297579</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297579">Oliveira et al. (2001)</a> concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Sato, N., Katsumata, N., Kagami, M., Hasegawa, T., Hori, N., Kawakita, S., Minowada, S., Shimotsuka, A., Shishiba, Y., Yokozawa, M., Yasuda, T., Nagasaki, K., Hasegawa, D., Hasegawa, Y., Tachibana, K., Naiki, Y., Horikawa, R., Tanaka, T., Ogata, T. <strong>Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.</strong> J. Clin. Endocr. Metab. 89: 1079-1088, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001591</a>] [<a href="https://doi.org/10.1210/jc.2003-030476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001591">Sato et al. (2004)</a> studied 25 male and 3 female Japanese individuals, aged 10 to 53 years, with Kallmann syndrome. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (<a href="/entry/136350">136350</a>) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and dental agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001591" 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="#7" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (<a href="/entry/308700#0012">308700.0012</a>) and the other in the PROKR2 gene (<a href="/entry/607123#0001">607123.0001</a>), raising the possibility of digenic inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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="#26" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> investigated 80 Brazilian patients with isolated hypogonadotropic hypogonadism (IHH), 46 of whom had olfactory abnormalities, for mutations in the KAL1 and FGFR1 genes. Two novel mutations in the KAL1 gene were found among the 46 patients with Kallmann syndrome (<a href="/entry/300386#0013">300386.0013</a> and <a href="/entry/300386#0014">300386.0014</a>). Eight novel FGFR1 mutations were found in 8 patients with Kallmann syndrome and in 1 with IHH and normal olfactory status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>) who was heterozygous for a missense mutation in the SEMA3A gene (<a href="/entry/603961">603961</a>), <a href="#10" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> also identified heterozygosity for a missense mutation in KAL1. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<p>In a patient and his brother with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#2" class="mim-tip-reference" title="Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A. <strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong> New Eng. J. Med. 326: 1752-1755, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>] [<a href="https://doi.org/10.1056/NEJM199206253262606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1594017">Bick et al. (1992)</a> detected a 3,300-bp deletion in the KALIG1 (KAL1) gene. <a href="#2" class="mim-tip-reference" title="Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A. <strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong> New Eng. J. Med. 326: 1752-1755, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>] [<a href="https://doi.org/10.1056/NEJM199206253262606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1594017">Bick et al. (1992)</a> studied 77 families in which one or more men had hypogonadotropic hypogonadism, characterized by hypogonadism and low serum concentrations of testosterone, luteinizing hormone, and follicle-stimulating hormone. None had evidence of deficiency of any other pituitary hormone or of a hypothalamic or pituitary mass lesion. Among the 77 families, the probands had anosmia in 52, hyposmia in 7, and a normal sense of smell in 18. In 10 of the families some affected members were brothers, and in 6 families some belonged to at least 2 generations related through female members, indicating a pattern of X-linked inheritance. In only 1 family was an abnormality on Southern blot analysis discovered. <a href="#2" class="mim-tip-reference" title="Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A. <strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong> New Eng. J. Med. 326: 1752-1755, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>] [<a href="https://doi.org/10.1056/NEJM199206253262606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1594017">Bick et al. (1992)</a> demonstrated that this patient and his brother had inherited from their mother a 3,300-bp deletion entirely confined within the 210-kb KALIG1 gene. They sequenced the 5-prime and 3-prime boundaries of the deleted region. A 6-bp homology (CAAATT) was found at the deletion breakpoint. It is possible that this short stretch of sequence homology was involved in the molecular mechanism that underlay the event producing the deletion. Similar nonhomologous recombinations as the basis of intragenic deletions have been postulated (<a href="#27" class="mim-tip-reference" title="Woods-Samuels, P., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Nonhomologous recombination in the human genome: deletions in the human factor VIII gene.</strong> Genomics 10: 94-101, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1904396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1904396</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90489-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1904396">Woods-Samuels et al., 1991</a>; <a href="#1" class="mim-tip-reference" title="Bernatowicz, L. F., Li, X.-M., Carrozzo, R., Ballabio, A., Mohandas, T., Yen, P. H., Shapiro, L. J. <strong>Sequence analysis of a partial deletion of the human steroid sulfatase gene reveals 3 bp of homology at deletion breakpoints.</strong> Genomics 13: 892-893, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639422</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90179-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639422">Bernatowicz et al., 1992</a>). The deletion included the penultimate exon which encodes one of the domains of the KALIG1 gene that is homologous with molecules involved in neural cell adhesion. In this family, 1 brother was born with microphallus, scrotal hypoplasia, and an undescended testis. His brother had normal genitalia at birth, but by 4 months of age his testes had retracted and his penis appeared involuted, closely resembling his brother's genitalia at the same age. Both had anosmia; their mother had a normal sense of smell. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1904396+1594017+1639422" 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">rs137852512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852512;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=rs137852512" 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=rs137852512" 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=RCV000010686" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010686" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010686</a>
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<p><a href="#12" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., del Castillo, I., Cohen-Salmon, M., Legouis, R., Blanchard, S., Compain, S., Bouloux, P., Kirk, J., Moraine, C., Chaussain, J.-L., Weissenbach, J., Petit, C. <strong>X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.</strong> Proc. Nat. Acad. Sci. 89: 8190-8194, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518845</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518845">Hardelin et al. (1992)</a> sought intragenic mutations in the KAL candidate gene in 18 unrelated patients with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>) patients. With the PCR, 2 exons of the gene were amplified in genomic DNA. They identified 3 different base substitutions--all leading to a stop codon--and 1 single-base deletion responsible for a frameshift. In 1 patient with a rather extensively affected family, they found a TGG-to-TGA transition at codon 237 converting tryptophan to stop (W237X). In addition to bilateral cryptorchidism and anosmia, the boy had synkinesia, minor motor epilepsy, and unilateral renal aplasia. A brother who had died at 1 day of age had only one kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518845" 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">rs137852513 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852513;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=rs137852513" 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=rs137852513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>) in whom micropenis and bilateral cryptorchidism was recognized at birth and who later showed anosmia, typical mirror movements of the hands (bimanual synkinesia) and mild bilateral pes cavus, <a href="#12" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., del Castillo, I., Cohen-Salmon, M., Legouis, R., Blanchard, S., Compain, S., Bouloux, P., Kirk, J., Moraine, C., Chaussain, J.-L., Weissenbach, J., Petit, C. <strong>X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.</strong> Proc. Nat. Acad. Sci. 89: 8190-8194, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518845</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518845">Hardelin et al. (1992)</a> found a CGA-to-TGA transition at codon 257 resulting in a change of arginine to stop (R257X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518845" 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>.0004 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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">rs137852514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852514;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=rs137852514" 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=rs137852514" 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=RCV000010688" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010688" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010688</a>
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<p>In an 11-year-old boy with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>) including unilateral cryptorchidism, anosmia, left ptosis, synkinesia, and unilateral renal aplasia, <a href="#12" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., del Castillo, I., Cohen-Salmon, M., Legouis, R., Blanchard, S., Compain, S., Bouloux, P., Kirk, J., Moraine, C., Chaussain, J.-L., Weissenbach, J., Petit, C. <strong>X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.</strong> Proc. Nat. Acad. Sci. 89: 8190-8194, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518845</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518845">Hardelin et al. (1992)</a> found a TGG-to-TGA transition resulting in conversion of tryptophan-258 to stop (W258X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518845" 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>.0005 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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ANOS1, 1-BP DEL, PRO277FS
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2146817110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146817110;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=rs2146817110" 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=rs2146817110" 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=RCV000010689" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010689" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010689</a>
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</span>
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<p>In an 8-year-old boy with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>) including micropenis, bilateral cryptorchidism, anosmia, and bilateral pes cavus, <a href="#12" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., del Castillo, I., Cohen-Salmon, M., Legouis, R., Blanchard, S., Compain, S., Bouloux, P., Kirk, J., Moraine, C., Chaussain, J.-L., Weissenbach, J., Petit, C. <strong>X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.</strong> Proc. Nat. Acad. Sci. 89: 8190-8194, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518845</a>] [<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518845">Hardelin et al. (1992)</a> found deletion of one C from codon 277 (CCC-to-CC, which normally codes for proline) resulting in frameshift. The brother of the patient also had Kallmann syndrome and marked pes cavus, and both had high-arched palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518845" 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 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, EX3-5DEL
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</div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010690" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010690" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010690</a>
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</span>
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<p><a href="#17" class="mim-tip-reference" title="Maya-Nunez, G., Cuevas-Covarrubias, S., Zenteno, J. C., Ulloa-Aguirre, A., Kofman-Alfaro, S., Mendez, J. P. <strong>Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene.</strong> Clin. Endocr. 48: 713-718, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9713559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9713559</a>] [<a href="https://doi.org/10.1046/j.1365-2265.1998.00406.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9713559">Maya-Nunez et al. (1998)</a> found KAL gene defects in 7 of 12 unrelated males with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>). One had a deletion from exon 3 to exon 5. The deletion comprised only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprised part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9713559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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ANOS1, GLU514LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852515;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=rs137852515" 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=rs137852515" 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=RCV000010691" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010691" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010691</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p><a href="#18" class="mim-tip-reference" title="Maya-Nunez, G., Zenteno, J. C., Ulloa-Aguirre, A., Kofman-Alfaro, S., Mendez, J. P. <strong>A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann's syndrome.</strong> J. Clin. Endocr. Metab. 83: 1650-1653, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9589672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9589672</a>] [<a href="https://doi.org/10.1210/jcem.83.5.4817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9589672">Maya-Nunez et al. (1998)</a> found KAL gene defects in 7 of 12 unrelated males with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>). Six patients had a previously unidentified missense mutation in exon 11, which was a G-to-A transition at codon 514 (GAA to AAA) resulting in a glu514-to-lys substitution (E514K). The fact that the same missense mutation was found in 6 of the 12 patients indicated that the mutation was derived from a common ancestor or resulted from a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589672" 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 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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</h4>
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ANOS1, EX5DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2146819139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146819139;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=rs2146819139" 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=rs2146819139" 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=RCV000010692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010692</a>
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</span>
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</div>
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<p>In a male patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#23" class="mim-tip-reference" title="Soderlund, D., Canto, P., Mendez, J. P. <strong>Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome.</strong> J. Clin. Endocr. Metab. 87: 2589-2592, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050219</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050219">Soderlund et al. (2002)</a> identified a complete deletion of exon 5 of the KAL1 gene, which occurred within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050219" 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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</h4>
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ANOS1, 11-BP DUP, NT158
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2146919315 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146919315;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=rs2146919315" 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=rs2146919315" 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=RCV000010693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010693</a>
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</span>
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<p>In a male patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#23" class="mim-tip-reference" title="Soderlund, D., Canto, P., Mendez, J. P. <strong>Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome.</strong> J. Clin. Endocr. Metab. 87: 2589-2592, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050219</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050219">Soderlund et al. (2002)</a> identified a novel duplication of nucleotides 158-168 in exon 1 of the KAL1 gene; this 11-bp insertion caused a termination codon (TGA) within the same exon. The duplication was located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or by stopping the translation at the stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050219" 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="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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</span>
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</h4>
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</div>
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ANOS1, ARG262TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852516;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=rs137852516" 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=rs137852516" 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=RCV000010694 OR RCV003314550" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010694, RCV003314550" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010694...</a>
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<p>In a male patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#23" class="mim-tip-reference" title="Soderlund, D., Canto, P., Mendez, J. P. <strong>Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome.</strong> J. Clin. Endocr. Metab. 87: 2589-2592, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050219</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050219">Soderlund et al. (2002)</a> identified a novel arg262-to-ter (R262X) mutation in exon 6 of the KAL1 gene. The stop codon in exon 6 was located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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ANOS1, EX3-13 DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010695" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010695" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010695</a>
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<p><a href="#16" class="mim-tip-reference" title="Massin, N., Pecheux, C., Eloit, C., Bensimon, J.-L., Galey, J., Kuttenn, F., Hardelin, J.-P., Dode, C., Touraine, P. <strong>X-chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.</strong> J. Clin. Endocr. Metab. 88: 2003-2008, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12727945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12727945</a>] [<a href="https://doi.org/10.1210/jc.2002-021981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12727945">Massin et al. (2003)</a> described clinical heterogeneity in 3 brothers with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>) who carried a large deletion (exons 3-13) in KAL1. All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727945" 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 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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ANOS1, SER396LEU
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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> rs137852517 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852517;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/rs137852517?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=rs137852517" 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=rs137852517" 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=RCV000010696 OR RCV002247315 OR RCV003436922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010696, RCV002247315, RCV003436922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010696...</a>
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<p>In a patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#7" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. <strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong> PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>] [<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> identified heterozygosity for a ser396-to-leu mutation in the KAL1 gene (S396L) and heterozygosity for a leu173-to-arg mutation in the PROKR2 gene (L173R; <a href="/entry/607123#0001">607123.0001</a>). The mutation in the KAL1 gene modifies the first amino acid residue of the linker between the second and third fibronectin-like type III repeats of the predicted protein; this residue is conserved among orthologous proteins from vertebrates and invertebrates. The mutation in the PROKR2 gene was identified in 6 unrelated Kallmann syndrome patients. Neither mutation was found in control individuals, raising the possibility of digenic inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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>.0013 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
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ANOS1, EX3-6 DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010697</a>
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<p>In a Brazilian patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#26" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> detected a sporadic intragenic deletion of exons 3 through 6 of the KAL1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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">rs387906427 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906427;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=rs387906427" 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=rs387906427" 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=RCV000010698" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010698" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010698</a>
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<p>In a Brazilian patient with Kallmann syndrome (HH1; <a href="/entry/308700">308700</a>), <a href="#26" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> detected a G-to-T transversion in the splice donor site of intron 7 of the KAL1 gene, expected to result in splicing aberration. The patient had 4 maternal uncles with Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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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Bernatowicz, L. F., Li, X.-M., Carrozzo, R., Ballabio, A., Mohandas, T., Yen, P. H., Shapiro, L. J.
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<strong>Sequence analysis of a partial deletion of the human steroid sulfatase gene reveals 3 bp of homology at deletion breakpoints.</strong>
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Genomics 13: 892-893, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639422</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90179-v" target="_blank">Full Text</a>]
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Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A.
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<strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong>
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New Eng. J. Med. 326: 1752-1755, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1594017" 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/10.1056/NEJM199206253262606" target="_blank">Full Text</a>]
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Bulow, H. E., Berry, K. L., Topper, L. H., Peles, E., Hobert, O.
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<strong>Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.</strong>
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[<a href="https://doi.org/10.1073/pnas.092128099" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/353529a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1360" target="_blank">Full Text</a>]
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Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., Jr., Vallejo, M.
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<strong>The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.</strong>
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J. Clin. Endocr. Metab. 86: 1532-1538, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297579" 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/10.1210/jcem.86.4.7420" 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="20" class="mim-anchor"></a>
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<a id="Parenti1995" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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|
Parenti, G., Rizzolo, M. G., Ghezzi, M., Di Maio, S., Sperandeo, M. P., Incerti, B., Franco, B., Ballabio, A., Andria, G.
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<strong>Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene.</strong>
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Am. J. Med. Genet. 57: 476-478, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677154</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677154" 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/ajmg.1320570323" 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="21" class="mim-anchor"></a>
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<a id="Rugarli1996" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Rugarli, E. I., Ghezzi, C., Valsecchi, V., Ballabio, A.
|
|
<strong>The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component.</strong>
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Hum. Molec. Genet. 5: 1109-1115, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842728</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8842728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/5.8.1109" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Sato2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sato, N., Katsumata, N., Kagami, M., Hasegawa, T., Hori, N., Kawakita, S., Minowada, S., Shimotsuka, A., Shishiba, Y., Yokozawa, M., Yasuda, T., Nagasaki, K., Hasegawa, D., Hasegawa, Y., Tachibana, K., Naiki, Y., Horikawa, R., Tanaka, T., Ogata, T.
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<strong>Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.</strong>
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J. Clin. Endocr. Metab. 89: 1079-1088, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001591" 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/10.1210/jc.2003-030476" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Soderlund2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soderlund, D., Canto, P., Mendez, J. P.
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<strong>Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome.</strong>
|
|
J. Clin. Endocr. Metab. 87: 2589-2592, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050219</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050219" 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/10.1210/jcem.87.6.8611" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Soussi-Yanicostas2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soussi-Yanicostas, N., de Castro, F., Julliard, A. K., Perfettini, I., Chedotal, A., Petit, C.
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<strong>Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons.</strong>
|
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Cell 109: 217-228, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007408</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007408" 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/s0092-8674(02)00713-4" target="_blank">Full Text</a>]
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Soussi-Yanicostas1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soussi-Yanicostas, N., Hardelin, J.-P., del Mar Arroyo-Jimenez, M., Ardouin, O., Legouis, R., Levilliers, J., Traincard, F., Betton, J.-M., Cabanie, L., Petit, C.
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<strong>Initial characterization of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system.</strong>
|
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J. Cell Sci. 109: 1749-1757, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8832397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8832397</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8832397" 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/10.1242/jcs.109.7.1749" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Trarbach2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C.
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<strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong>
|
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J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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/10.1210/jc.2005-2793" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Woods-Samuels1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Woods-Samuels, P., Kazazian, H. H., Jr., Antonarakis, S. E.
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<strong>Nonhomologous recombination in the human genome: deletions in the human factor VIII gene.</strong>
|
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Genomics 10: 94-101, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1904396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1904396</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1904396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90489-2" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 10/28/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 9/25/2012
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf : 3/9/2011
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/21/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/20/2022<br>carol : 04/07/2020<br>carol : 12/23/2019<br>carol : 02/09/2016<br>carol : 10/28/2013<br>carol : 10/4/2012<br>carol : 9/25/2012<br>carol : 9/25/2012<br>carol : 9/21/2012<br>carol : 9/21/2012<br>terry : 9/7/2012<br>alopez : 3/10/2011<br>alopez : 3/10/2011
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</span>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300836
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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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ANOSMIN 1; ANOS1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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KALLMANN SYNDROME INTERVAL GENE 1; KALIG1<br />
|
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ADHESION MOLECULE-LIKE, X-LINKED; ADMLX<br />
|
|
KAL1 GENE; KAL1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: ANOS1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: Xp22.31
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Genomic coordinates <span class="small">(GRCh38)</span> : X:8,528,874-8,732,137 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
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Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
Xp22.31
|
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</span>
|
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</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
308700
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
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<p>The KAL1 gene encodes a protein, anosmin, that plays a key role in the migration of GNRH (152760) neurons and olfactory nerves to the hypothalamus (summary by Cariboni et al., 2004). </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>Legouis et al. (1991) sequenced 67 kb of genomic DNA within the X-linked Kallmann syndrome (308700) critical region. They found 2 candidate exons, identified by multiparameter computer programs, in a cDNA encoding a protein of 679 amino acids. This candidate gene, ADMLX (adhesion molecule-like, X-linked), was interrupted in its 3-prime coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. The predicted protein sequence showed homologies with the fibronectin type III (FN3) repeat. Thus, ADMLX encodes a putative adhesion molecule consistent with the defect of embryonic neuronal migration. </p><p>Franco et al. (1991) showed that the KALIG1 gene shares homology with molecules involved in cell adhesion and axonal pathfinding, further supporting the notion that a molecular defect in this gene causes the neuronal migration defect underlying Kallmann syndrome. </p><p>Legouis et al. (1993) determined the entire coding sequence of chicken and quail KAL cDNAs and demonstrated an overall identity of 73% and 72%, respectively, with human KAL cDNA. This corresponds to 76% and 75% identity at the protein level. </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>Del Castillo et al. (1992) demonstrated that the KAL1 gene contains 14 exons spanning 120 to 200 kb that correlate with the distribution of domains in the predicted protein including 4 fibronectin type III repeats. The homologous locus, KALP, on Yq11 has several large deletions and a number of small insertions, deletions, and base substitutions which indicate that it is a nonprocessed pseudogene. The sequence divergence between KAL1 and KALP in humans, and the chromosomal location of KAL homologous sequences in other primates, suggested that KALP and the steroid sulfatase pseudogene (see 300747) on Yq11 were involved in the same rearrangement event on the Y chromosome during primate evolution. Incerti et al. (1992), who localized the KALP pseudogene to Yq11.2, came to similar conclusions. </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>Franco et al. (1991) mapped a gene, which they called KALIG1 (Kallmann syndrome interval gene-1), to the Kallmann syndrome critical region on chromosome Xp22.3. </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>Soussi-Yanicostas et al. (1996) showed that the KAL protein is N-glycosylated, secreted in the cell culture medium, and localized at the cell surface. Upon transfection of Chinese hamster ovary (CHO) cells with human KAL cDNA, the corresponding encoded protein was produced. Several lines of evidence indicated that heparan-sulfate chains of proteoglycan(s) are involved in the binding of the KAL protein to the cell membrane. The authors generated polyclonal and monoclonal antibodies to the purified KAL protein. With these, they detected and characterized the protein encoded by the KAL gene in the chicken central nervous system at late stages of embryonic development. The protein is synthesized by definite neuronal cell populations, including Purkinje cells in the cerebellum, mitral cells in the olfactory bulbs, and several subpopulations in the optic tectum, and the striatum. The protein, with an approximate molecular mass of 100 kD, was named anosmin-1 by the authors in reference to the deficiency of the sense of smell that characterizes Kallmann disease. Anosmin-1 was thought to be an extracellular matrix component. Since heparin treatment of cell membrane fractions from cerebellum and tectum resulted in the release of the protein, Soussi-Yanicostas et al. (1996) suggested that 1 or several heparan-sulfate proteoglycans are involved in the binding of anosmin-1 to the membranes in vivo. </p><p>Rugarli et al. (1996) reported that KAL encodes a predicted 680-amino acid polypeptide with a protease inhibitor domain that is followed by 4 fibronectin type III repeats. Because the low abundance of this protein hampered biochemical characterization, they carried out transfection experiments to overexpress human and chick KAL in eukaryotic cells. Rugarli et al. (1996) reported that KAL is localized on the cell surface and it appears to be secreted as a diffusible molecule. They demonstrated that KAL undergoes proteolytic cleavage to yield a diffusible component and that this diffusible form is incorporated into the extracellular matrix. Rugarli et al. (1996) postulated that once incorporated into the extracellular matrix of the olfactory bulb, KAL might promote the ultimate migration and target recognition of olfactory axons. </p><p>Soussi-Yanicostas et al. (2002) showed that anti-anosmin-1 antibodies blocked the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhanced axonal branching of these dissociated neurons in culture. Coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrated that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. The authors concluded that anosmin-1 has a dual branch-promoting and guidance activity and is involved in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex. </p><p>Bulow et al. (2002) showed that expression of the C. elegans homolog of KAL1 in selected sensory and interneuron classes caused a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans Kal1 expression caused a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities required different domains of the KAL1 protein. In a genetic modifier screen, Bulow et al. (2002) isolated several loci that either suppressed or enhanced the Kal1-induced axonal defects, 1 of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan 6-O-sulfotransferase (604846). Bulow et al. (2002) hypothesized that KAL1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting. </p><p>Based on their finding that loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1; 136350) cause an autosomal form of hypogonadotropic hypogonadism with anosmia (HH2; Kallmann syndrome, 147950), Dode et al. (2003) proposed that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling, that there is an interaction between anosmin-1 and FGFR1, and that the higher prevalence of the disease in males is due to gender difference in anosmin-1 dosage, because KAL1 partially escapes X inactivation. </p><p>Cariboni et al. (2004) showed a direct action of anosmin-1 on the migratory activity of GNRH (152760) neurons. They found that exposing immortalized migrating GnRH neurons to anosmin-1-enriched media produced a cell-specific chemotactic response. Mutant anosmin-1 (308700.0007)-enriched media did not affect the chemomigration of GnRH neurons. Anosmin bound to the cell surface of neurons by interacting with the heparan sulfate proteoglycans, and the chemotactic effect of anosmin-1-enriched media could be specifically blocked by heparin or by heparitinase pretreatment. </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>Cytogenetics</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>Maya-Nunez et al. (1998) described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (STS; 300747). The 20-year-old subject had hypogonadism and anosmia, as well as generalized ichthyosis (see 308100). They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the 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>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>In a patient and his brother with Kallmann syndrome (HH1; 308700), Bick et al. (1992) detected a 3,300-bp deletion in the KAL1 gene (300836.0001). </p><p>Hardelin et al. (1993) reported results of a mutation search of the KAL1 gene in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann syndrome patients; 6 of 11 males with identified alterations of the KAL gene showed this feature. </p><p>Parenti et al. (1995) reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposmia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear. </p><p>Georgopoulos et al. (1997) determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency, a heritable condition characterized by a functional deficit in GNRH secretion. Only 1 of 21 (5%) of these patients had a KAL1 mutation (a deletion of 14 bases starting at codon 464); this patient also had anosmia (Kallmann syndrome). In each of 3 unrelated patients from families with an X-linked mode of inheritance, 3 different mutations were detected. These were a single-base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution, and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. Georgopoulos et al. (1997) suggested that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low. </p><p>Oliveira et al. (2001) examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). Oliveira et al. (2001) concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes. </p><p>Sato et al. (2004) studied 25 male and 3 female Japanese individuals, aged 10 to 53 years, with Kallmann syndrome. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (136350) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and dental agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. </p><p>Dode et al. (2006) described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (308700.0012) and the other in the PROKR2 gene (607123.0001), raising the possibility of digenic inheritance. </p><p>Trarbach et al. (2006) investigated 80 Brazilian patients with isolated hypogonadotropic hypogonadism (IHH), 46 of whom had olfactory abnormalities, for mutations in the KAL1 and FGFR1 genes. Two novel mutations in the KAL1 gene were found among the 46 patients with Kallmann syndrome (300386.0013 and 300386.0014). Eight novel FGFR1 mutations were found in 8 patients with Kallmann syndrome and in 1 with IHH and normal olfactory status. </p><p>In a patient with anosmic hypogonadotropic hypogonadism (HH16; 614897) who was heterozygous for a missense mutation in the SEMA3A gene (603961), Hanchate et al. (2012) also identified heterozygosity for a missense mutation in KAL1. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, 3,300-BP DEL
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<br />
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ClinVar: RCV000010685
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient and his brother with Kallmann syndrome (HH1; 308700), Bick et al. (1992) detected a 3,300-bp deletion in the KALIG1 (KAL1) gene. Bick et al. (1992) studied 77 families in which one or more men had hypogonadotropic hypogonadism, characterized by hypogonadism and low serum concentrations of testosterone, luteinizing hormone, and follicle-stimulating hormone. None had evidence of deficiency of any other pituitary hormone or of a hypothalamic or pituitary mass lesion. Among the 77 families, the probands had anosmia in 52, hyposmia in 7, and a normal sense of smell in 18. In 10 of the families some affected members were brothers, and in 6 families some belonged to at least 2 generations related through female members, indicating a pattern of X-linked inheritance. In only 1 family was an abnormality on Southern blot analysis discovered. Bick et al. (1992) demonstrated that this patient and his brother had inherited from their mother a 3,300-bp deletion entirely confined within the 210-kb KALIG1 gene. They sequenced the 5-prime and 3-prime boundaries of the deleted region. A 6-bp homology (CAAATT) was found at the deletion breakpoint. It is possible that this short stretch of sequence homology was involved in the molecular mechanism that underlay the event producing the deletion. Similar nonhomologous recombinations as the basis of intragenic deletions have been postulated (Woods-Samuels et al., 1991; Bernatowicz et al., 1992). The deletion included the penultimate exon which encodes one of the domains of the KALIG1 gene that is homologous with molecules involved in neural cell adhesion. In this family, 1 brother was born with microphallus, scrotal hypoplasia, and an undescended testis. His brother had normal genitalia at birth, but by 4 months of age his testes had retracted and his penis appeared involuted, closely resembling his brother's genitalia at the same age. Both had anosmia; their mother had a normal sense of smell. </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 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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|
ANOS1, TRP237TER
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<br />
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SNP: rs137852512,
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ClinVar: RCV000010686
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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>Hardelin et al. (1992) sought intragenic mutations in the KAL candidate gene in 18 unrelated patients with Kallmann syndrome (HH1; 308700) patients. With the PCR, 2 exons of the gene were amplified in genomic DNA. They identified 3 different base substitutions--all leading to a stop codon--and 1 single-base deletion responsible for a frameshift. In 1 patient with a rather extensively affected family, they found a TGG-to-TGA transition at codon 237 converting tryptophan to stop (W237X). In addition to bilateral cryptorchidism and anosmia, the boy had synkinesia, minor motor epilepsy, and unilateral renal aplasia. A brother who had died at 1 day of age had only one kidney. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, ARG257TER
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<br />
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|
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SNP: rs137852513,
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ClinVar: RCV000010687
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with Kallmann syndrome (HH1; 308700) in whom micropenis and bilateral cryptorchidism was recognized at birth and who later showed anosmia, typical mirror movements of the hands (bimanual synkinesia) and mild bilateral pes cavus, Hardelin et al. (1992) found a CGA-to-TGA transition at codon 257 resulting in a change of arginine to stop (R257X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, TRP258TER
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<br />
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SNP: rs137852514,
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ClinVar: RCV000010688
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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 an 11-year-old boy with Kallmann syndrome (HH1; 308700) including unilateral cryptorchidism, anosmia, left ptosis, synkinesia, and unilateral renal aplasia, Hardelin et al. (1992) found a TGG-to-TGA transition resulting in conversion of tryptophan-258 to stop (W258X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, 1-BP DEL, PRO277FS
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<br />
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SNP: rs2146817110,
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ClinVar: RCV000010689
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old boy with Kallmann syndrome (HH1; 308700) including micropenis, bilateral cryptorchidism, anosmia, and bilateral pes cavus, Hardelin et al. (1992) found deletion of one C from codon 277 (CCC-to-CC, which normally codes for proline) resulting in frameshift. The brother of the patient also had Kallmann syndrome and marked pes cavus, and both had high-arched palate. </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>.0006 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, EX3-5DEL
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<br />
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ClinVar: RCV000010690
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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>Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males with Kallmann syndrome (HH1; 308700). One had a deletion from exon 3 to exon 5. The deletion comprised only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprised part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, GLU514LYS
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<br />
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SNP: rs137852515,
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ClinVar: RCV000010691
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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>Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males with Kallmann syndrome (HH1; 308700). Six patients had a previously unidentified missense mutation in exon 11, which was a G-to-A transition at codon 514 (GAA to AAA) resulting in a glu514-to-lys substitution (E514K). The fact that the same missense mutation was found in 6 of the 12 patients indicated that the mutation was derived from a common ancestor or resulted from a mutation hotspot. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, EX5DEL
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<br />
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SNP: rs2146819139,
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ClinVar: RCV000010692
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with Kallmann syndrome (HH1; 308700), Soderlund et al. (2002) identified a complete deletion of exon 5 of the KAL1 gene, which occurred within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</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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ANOS1, 11-BP DUP, NT158
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<br />
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SNP: rs2146919315,
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ClinVar: RCV000010693
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with Kallmann syndrome (HH1; 308700), Soderlund et al. (2002) identified a novel duplication of nucleotides 158-168 in exon 1 of the KAL1 gene; this 11-bp insertion caused a termination codon (TGA) within the same exon. The duplication was located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or by stopping the translation at the stop codon. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ANOS1, ARG262TER
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<br />
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SNP: rs137852516,
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ClinVar: RCV000010694, RCV003314550
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a male patient with Kallmann syndrome (HH1; 308700), Soderlund et al. (2002) identified a novel arg262-to-ter (R262X) mutation in exon 6 of the KAL1 gene. The stop codon in exon 6 was located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein. </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>.0011 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
ANOS1, EX3-13 DEL
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<br />
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|
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ClinVar: RCV000010695
|
|
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|
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</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>Massin et al. (2003) described clinical heterogeneity in 3 brothers with Kallmann syndrome (HH1; 308700) who carried a large deletion (exons 3-13) in KAL1. All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome. </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>.0012 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ANOS1, SER396LEU
|
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|
|
<br />
|
|
|
|
SNP: rs137852517,
|
|
|
|
|
|
gnomAD: rs137852517,
|
|
|
|
|
|
ClinVar: RCV000010696, RCV002247315, RCV003436922
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Kallmann syndrome (HH1; 308700), Dode et al. (2006) identified heterozygosity for a ser396-to-leu mutation in the KAL1 gene (S396L) and heterozygosity for a leu173-to-arg mutation in the PROKR2 gene (L173R; 607123.0001). The mutation in the KAL1 gene modifies the first amino acid residue of the linker between the second and third fibronectin-like type III repeats of the predicted protein; this residue is conserved among orthologous proteins from vertebrates and invertebrates. The mutation in the PROKR2 gene was identified in 6 unrelated Kallmann syndrome patients. Neither mutation was found in control individuals, raising the possibility of digenic inheritance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ANOS1, EX3-6 DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010697
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Brazilian patient with Kallmann syndrome (HH1; 308700), Trarbach et al. (2006) detected a sporadic intragenic deletion of exons 3 through 6 of the KAL1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HYPOGONADOTROPIC HYPOGONADISM 1 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ANOS1, IVS7, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906427,
|
|
|
|
|
|
|
|
ClinVar: RCV000010698
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Brazilian patient with Kallmann syndrome (HH1; 308700), Trarbach et al. (2006) detected a G-to-T transversion in the splice donor site of intron 7 of the KAL1 gene, expected to result in splicing aberration. The patient had 4 maternal uncles with Kallmann syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
|
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<li>
|
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<p class="mim-text-font">
|
|
Bernatowicz, L. F., Li, X.-M., Carrozzo, R., Ballabio, A., Mohandas, T., Yen, P. H., Shapiro, L. J.
|
|
<strong>Sequence analysis of a partial deletion of the human steroid sulfatase gene reveals 3 bp of homology at deletion breakpoints.</strong>
|
|
Genomics 13: 892-893, 1992.
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[PubMed: 1639422]
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[Full Text: https://doi.org/10.1016/0888-7543(92)90179-v]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A.
|
|
<strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong>
|
|
New Eng. J. Med. 326: 1752-1755, 1992.
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[PubMed: 1594017]
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[Full Text: https://doi.org/10.1056/NEJM199206253262606]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bulow, H. E., Berry, K. L., Topper, L. H., Peles, E., Hobert, O.
|
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<strong>Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.</strong>
|
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Proc. Nat. Acad. Sci. 99: 6346-6351, 2002.
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[PubMed: 11983919]
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[Full Text: https://doi.org/10.1073/pnas.092128099]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cariboni, A., Pimpinelli, F., Colamarino, S., Zaninetti, R., Piccolella, M., Rumio, C., Piva, F., Rugarli, E. I., Maggi, R.
|
|
<strong>The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons.</strong>
|
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Hum. Molec. Genet. 13: 2781-2791, 2004.
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[PubMed: 15471890]
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[Full Text: https://doi.org/10.1093/hmg/ddh309]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
del Castillo, I., Cohen-Salmon, M., Blanchard, S., Lutfalla, G., Petit, C.
|
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<strong>Structure of the X-linked Kallmann syndrome gene and its homologous pseudogene on the Y chromosome.</strong>
|
|
Nature Genet. 2: 305-310, 1992.
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[PubMed: 1303284]
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[Full Text: https://doi.org/10.1038/ng1292-305]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others.
|
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<strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong>
|
|
Nature Genet. 33: 463-465, 2003.
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[PubMed: 12627230]
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[Full Text: https://doi.org/10.1038/ng1122]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
|
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<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
|
|
PLoS Genet. 2: e175, 2006. Note: Electronic Article.
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|
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[PubMed: 17054399]
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[Full Text: https://doi.org/10.1371/journal.pgen.0020175]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., Brown, C. J., Willard, H. F., Lawrence, C., Persico, M. G., Camerino, G., Ballabio, A.
|
|
<strong>A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.</strong>
|
|
Nature 353: 529-536, 1991.
|
|
|
|
|
|
[PubMed: 1922361]
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|
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|
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[Full Text: https://doi.org/10.1038/353529a0]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Georgopoulos, N. A., Pralong, F. P., Seidman, C. E., Seidman, J. G., Crowley, W. F., Jr., Vallejo, M.
|
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<strong>Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.</strong>
|
|
J. Clin. Endocr. Metab. 82: 213-217, 1997.
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|
|
|
|
[PubMed: 8989261]
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|
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[Full Text: https://doi.org/10.1210/jcem.82.1.3692]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others.
|
|
<strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong>
|
|
PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 22927827]
|
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|
|
[Full Text: https://doi.org/10.1371/journal.pgen.1002896]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., Petit, C.
|
|
<strong>Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.</strong>
|
|
Hum. Molec. Genet. 2: 373-377, 1993.
|
|
|
|
|
|
[PubMed: 8504298]
|
|
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/2.4.373]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
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