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- *608894 - ABELSON HELPER INTEGRATION SITE 1; AHI1
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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">*608894</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608894">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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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000135541;t=ENST00000265602" 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=54806" 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=608894" 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=ENSG00000135541;t=ENST00000265602" 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_001134830,NM_001134831,NM_001134832,NM_001350503,NM_001350504,NM_017651,XM_011535910,XM_011535911,XM_017010979,XM_017010984,XM_024446480,XM_047418939,XM_047418940,XM_047418941,XM_047418942,XM_047418943,XM_047418944,XM_047418945,XM_047418946,XR_001743480,XR_007059276,XR_007059277,XR_007059278" 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_001134831" 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=608894" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=10597&isoform_id=10597_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/AHI1" 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/7019929,10436376,12053107,20797209,20797214,21750809,22252982,31542701,34190978,41350958,45502026,63101682,68989463,73921659,119568347,119568348,119568349,119568350,119568351,199559438,199559490,199559532,767943051,767943053,1034650636,1034650653,1179910147,1179910173,1370508262,2217361926,2217361928,2217361930,2217361932,2217361934,2217361939,2217361942,2217361944,2462609095,2462609097,2462609100,2462609102,2462609104,2462609106,2462609108,2462609110,2462609114,2462609116,2462609118,2462609120,2462609122,2462609124" 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/Q8N157" 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=54806" 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=ENSG00000135541;t=ENST00000265602" 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=AHI1" 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=AHI1" 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+54806" 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/AHI1" 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:54806" 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/54806" 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=chr6&hgg_gene=ENST00000265602.11&hgg_start=135283532&hgg_end=135497740&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:21575" 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:21575" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608894[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=608894[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/AHI1/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/ENSG00000135541" 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=AHI1" 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=AHI1" 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=AHI1" 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=AHI1&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/PA134874587" 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:21575" 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://www.mousephenotype.org/data/genes/MGI:87971" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/AHI1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:87971" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/54806/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=54806" 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://zfin.org/ZDB-GENE-060803-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=AHI1&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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608894
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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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ABELSON HELPER INTEGRATION SITE 1; AHI1
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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">
|
|
JOUBERIN
|
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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=AHI1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AHI1</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/6/884?start=-3&limit=10&highlight=884">6q23.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:135283532-135497740&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'})">6:135,283,532-135,497,740</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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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/6/884?start=-3&limit=10&highlight=884">
|
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6q23.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Joubert syndrome 3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/608629"> 608629 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/608894" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608894" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<p>AHI1 is a component of a protein complex in the basal body, a ring-like structure that functions in the transition zone at the base of cilia. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (<a href="#1" class="mim-tip-reference" title="Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. <strong>A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.</strong> Nature Cell Biol. 14: 61-72, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179047</a>] [<a href="https://doi.org/10.1038/ncb2410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179047">Chih et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22179047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching databases for sequences similar to mouse and rat Ahi1, <a href="#7" class="mim-tip-reference" title="Jiang, X., Hanna, Z., Kaouass, M., Girard, L., Jolicoeur, P. <strong>Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations.</strong> J. Virol. 76: 9046-9059, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12186888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12186888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12186888[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/10.1128/jvi.76.18.9046-9059.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12186888">Jiang et al. (2002)</a> identified 3 splice variants of human AHI1. Full-length human AHI1 contains at least 1,187 amino acids. Both the rodent and human proteins have 7 WD40 repeats and an SH3 domain, but human AHI1 contains an N-terminal coiled-coil domain not found in the rodent proteins. One of the human AHI1 splice variants encodes a protein lacking the SH3 domain. RT-PCR analysis of Jurkat human T cells identified splice variants exhibiting exon skipping in the 5-prime UTR. Northern blot analysis of mouse tissues detected several Ahi1 splice variants, with highest expression in brain and testis and very low expression in liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12186888" 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="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> noted that the AHI1 gene contains a coiled-coil domain in its N-terminal 140 amino acids. These amino acids and this domain are entirely missing in the predicted proteins of both mouse and rat, but are present in the predicted proteins of nonhuman primates and other mammals (cow, pig, dog, and cat). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" 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="Jiang, X., Zhao, Y., Chan, W.-Y., Vercauteren, S., Pang, E., Kennedy, S., Nicolini, F., Eaves, A., Eaves, C. <strong>Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia.</strong> Blood 103: 3897-3904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14751929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14751929</a>] [<a href="https://doi.org/10.1182/blood-2003-11-4026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14751929">Jiang et al. (2004)</a> found that expression of mouse and human AHI1 was highest in the most primitive types of normal hematopoietic cells and was downregulated during early differentiation. Cells from 28 patients with chronic myeloid leukemia (CML; <a href="/entry/608232">608232</a>) showed elevated AHI1 mRNA in all disease phases and at all stages of differentiation, including quiescent CD34 (<a href="/entry/142230">142230</a>)-positive cells and terminally differentiating cells. In the most primitive CML cells, transcripts of the 2 shorter isoforms of AHI1 were also increased. Although 15 of 16 human lymphoid and myeloid leukemic cell lines showed aberrant control of AHI1 expression, this was not seen in blasts obtained directly from 15 patients with acute Philadelphia chromosome-negative leukemia. <a href="#8" class="mim-tip-reference" title="Jiang, X., Zhao, Y., Chan, W.-Y., Vercauteren, S., Pang, E., Kennedy, S., Nicolini, F., Eaves, A., Eaves, C. <strong>Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia.</strong> Blood 103: 3897-3904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14751929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14751929</a>] [<a href="https://doi.org/10.1182/blood-2003-11-4026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14751929">Jiang et al. (2004)</a> concluded that downregulation of AHI1 expression is a conserved step in primitive normal hematopoietic cell differentiation and that perturbations in AHI1 expression may contribute to the development of specific types of human leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14751929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation analysis, <a href="#14" class="mim-tip-reference" title="Sheng, G., Xu, X., Lin, Y.-F., Wang, C.-E., Rong, J., Cheng, D., Peng, J., Jiang, X., Li, S.-H., Li, X.-J. <strong>Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.</strong> J. Clin. Invest. 118: 2785-2795, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18636121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18636121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18636121[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/10.1172/JCI35339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18636121">Sheng et al. (2008)</a> found that Ahi1 bound tightly to Hap1 (<a href="/entry/600947">600947</a>) in mouse brain lysates. Depletion of either protein reduced the amount of the other, and conversely, overexpression of either protein increased the endogenous level of the other, suggesting Ahi1 and Hap1 stabilize each other. Reduction of either Hap1 or Ahi1 also reduced the level of Trkb (NTRK2; <a href="/entry/600456">600456</a>) and Trkb signaling, as indicated by reduced phosphorylation of Erk (see <a href="/entry/601795">601795</a>) and Akt (see <a href="/entry/164730">164730</a>). <a href="#14" class="mim-tip-reference" title="Sheng, G., Xu, X., Lin, Y.-F., Wang, C.-E., Rong, J., Cheng, D., Peng, J., Jiang, X., Li, S.-H., Li, X.-J. <strong>Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.</strong> J. Clin. Invest. 118: 2785-2795, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18636121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18636121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18636121[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/10.1172/JCI35339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18636121">Sheng et al. (2008)</a> concluded that HAP1 and AHI1 maintain the level and signaling of TRKB in neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18636121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hsiao, Y.-C., Tong, Z. J., Westfall, J. E., Ault, J. G., Page-McCaw, P. S., Ferland, R. J. <strong>Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.</strong> Hum. Molec. Genet. 18: 3926-3941, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625297[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/10.1093/hmg/ddp335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625297">Hsiao et al. (2009)</a> showed that AHI1 regulated formation of the primary nonmotile cilium via its interaction with RAB8A (<a href="/entry/165040">165040</a>), a small GTPase critical for polarized membrane trafficking. Mouse Ahi1 protein localized to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In mice, RNAi knockdown of Ahi1 expression led to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a was destabilized and did not properly localize to the basal body. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. <a href="#5" class="mim-tip-reference" title="Hsiao, Y.-C., Tong, Z. J., Westfall, J. E., Ault, J. G., Page-McCaw, P. S., Ferland, R. J. <strong>Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.</strong> Hum. Molec. Genet. 18: 3926-3941, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625297[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/10.1093/hmg/ddp335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625297">Hsiao et al. (2009)</a> concluded that the distribution and functioning of RAB8A is regulated by AHI1, not only affecting cilium formation, but also vesicle transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (<a href="/entry/614144">614144</a>) in mouse IMCD3 cells and embryonic fibroblasts, <a href="#1" class="mim-tip-reference" title="Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. <strong>A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.</strong> Nature Cell Biol. 14: 61-72, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179047</a>] [<a href="https://doi.org/10.1038/ncb2410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179047">Chih et al. (2012)</a> identified several components of the B9d1-containing ciliary complex, including Tmem231 (<a href="/entry/614949">614949</a>), Tmem17 (<a href="/entry/614950">614950</a>), B9d2 (<a href="/entry/611951">611951</a>), Tctn1 (<a href="/entry/609863">609863</a>), Tctn2 (<a href="/entry/613846">613846</a>), Mks1 (<a href="/entry/609883">609883</a>), Ahi1, Cc2d2a (<a href="/entry/612013">612013</a>), and Kctd10 (<a href="/entry/613421">613421</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22179047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coimmunoprecipitation of transfected HEK293 cells, <a href="#15" class="mim-tip-reference" title="Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J. <strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong> J. Biol. Chem. 288: 13676-13694, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23532844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23532844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23532844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.420786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23532844">Tuz et al. (2013)</a> found that AHI1 interacted with NPHP1 (<a href="/entry/607100">607100</a>) and with HAP1. Gel filtration followed by Western blot analysis confirmed the interactions and suggested that AHI1 and NPHP1 form heterodimers of about 210 kD and heterotetramers of about 430 kD. AHI1 formed 470-kD heterotetramers, but not heterodimers, with HAP1. <a href="#15" class="mim-tip-reference" title="Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J. <strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong> J. Biol. Chem. 288: 13676-13694, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23532844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23532844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23532844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.420786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23532844">Tuz et al. (2013)</a> reported that the WD40 repeats of AHI1 interacted with the SH3 domain of NPHP1, and they found that the region between the coiled-coil domain and central WD40 repeat domain of AHI1 bound the N-terminal TATA-binding protein-interacting region of HAP1. Western blot and immunohistochemical analyses of Ahi1 -/- mouse brain showed that loss of Ahi1 reduced Hap1 content overall and eliminated Hap1 staining in the stigmoid body of hypothalamus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23532844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Jiang, X., Hanna, Z., Kaouass, M., Girard, L., Jolicoeur, P. <strong>Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations.</strong> J. Virol. 76: 9046-9059, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12186888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12186888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12186888[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/10.1128/jvi.76.18.9046-9059.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12186888">Jiang et al. (2002)</a> determined that the AHI1 gene contains at least 33 exons and spans 213.7 kb. The protein-coding sequence begins in exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12186888" 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="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> identified the AHI1 gene within a locus on chromosome 6q23.2-q23.3 to which Joubert syndrome (<a href="/entry/608629">608629</a>) had been mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" 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="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> carried out a genomewide screen in 3 Saudi Arabian pedigrees from the same geographic region with autosomal recessive Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>). The addition of another Saudi Arabian family and a pedigree from Turkey narrowed the region of shared homozygosity. Pooling of linkage data and lod scores from the 5 pedigrees resulted in a summed multipoint lod score of 8.36 and a maximum 2-point lod score of 6.31 (at recombination fraction = 0.0) at marker D6S1626. Sequencing of candidate genes in the minimal region of linkage identified 3 independent mutations in the AHI1 gene (<a href="#0001">608894.0001</a>-<a href="#0003">608894.0003</a>). It is remarkable that <a href="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> found homozygosity for 3 different mutations in the AHI1 gene in the 3 Saudi Arabian families living in the same geographic region. No mutation was identified in the Saudi Arabian family from another region or in the Turkish pedigree. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 3 consanguineous families with Joubert syndrome, some with cortical polymicrogyria, <a href="#2" class="mim-tip-reference" title="Dixon-Salazar, T., Silhavy, J. L., Marsh, S. E., Louie, C. M., Scott, L. C., Gururaj, A., Al-Gazali, L., Al-Tawari, A. A., Kayserili, H., Sztriha, L., Gleeson, J. G. <strong>Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria.</strong> Am. J. Hum. Genet. 75: 979-987, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467982[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/10.1086/425985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467982">Dixon-Salazar et al. (2004)</a> identified 1 missense and 2 frameshift mutations in the AHI1 gene. They designated the AHI1 protein Jouberin. The gene is expressed strongly in embryonic hindbrain and forebrain, and the data of <a href="#2" class="mim-tip-reference" title="Dixon-Salazar, T., Silhavy, J. L., Marsh, S. E., Louie, C. M., Scott, L. C., Gururaj, A., Al-Gazali, L., Al-Tawari, A. A., Kayserili, H., Sztriha, L., Gleeson, J. G. <strong>Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria.</strong> Am. J. Hum. Genet. 75: 979-987, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467982[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/10.1086/425985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467982">Dixon-Salazar et al. (2004)</a> suggested that AHI1 is required for both cerebellar and cortical development in humans. The authors pointed out that in a subset of patients with Joubert syndrome plus nephronophthisis, the phenotype is caused by mutation in the NPHP1 gene (<a href="/entry/607100#0005">607100.0005</a>). Nephrocystin, the protein encoded by NPHP1, contains an SH3 domain, suggesting that a shared pathway may be involved in these different forms of Joubert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a combination of haplotype analysis and gene sequencing, <a href="#13" class="mim-tip-reference" title="Parisi, M. A., Doherty, D., Eckert, M. L., Shaw, D. W. W., Ozyurek, H., Aysun, S., Giray, O., Al Swaid, A., Al Shahwan, S., Dohayan, N., Bakhsh, E., Indridason, O. S., Dobyns, W. B., Bennett, C. L., Chance, P. F., Glass, I. A. <strong>AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.</strong> J. Med. Genet. 43: 334-339, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155189</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155189[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/10.1136/jmg.2005.036608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155189">Parisi et al. (2006)</a> screened 117 probands with Joubert syndrome for mutations in the AHI1 gene and identified a total of 15 novel and 5 previously identified mutations in 19 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Fourteen of the mutation-positive families were consanguineous, but no single founder mutation was apparent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16155189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a> identified 15 different mutations (see, e.g., <a href="#0004">608894.0004</a>-<a href="#0006">608894.0006</a>) in the AHI1 gene in 11 patients from 10 families with Joubert syndrome. These patients accounted for 7.3% of 137 probands with the molar tooth sign and Joubert-related disorders. A phenotype-specific group of Joubert plus retinopathy had an AHI1 mutation frequency of 21.7% (5 of 23 probands). Clinical analysis indicated that AHI1 mutations were not associated with kidney or liver changes. Retinal abnormalities ranged from retinitis pigmentosa to blindness. There were 2 splice site mutations, 1 missense, and 12 truncating mutations, of which 11 were predicted to abolish all of the SH3 domain and all or part of the WD40 domain. In 2 Egyptian sibs (family MTI-229) with Joubert syndrome-3 originally reported by <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a>, <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> found that the causative AHI1 mutation was a homozygous missense change (S761L; <a href="#0011">608894.0011</a>) rather than a C-terminal deletion (c.3263delGG; <a href="#0004">608894.0004</a>). The missense mutation was found by homozygosity mapping and whole-exome sequencing. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. Expression of the c.3263delGG mutation in zebrafish did not cause any abnormalities, suggesting that the C-terminal SH3 domain of AHI1 is not required for normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25616960+16453322" 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="Louie, C. M., Caridi, G., Lopes, V. S., Brancati, F., Kispert, A., Lancaster, M. A., Schlossman, A. M., Otto, E. A., Leitges, M., Grone, H.-J., Lopez, I., Gudiseva, H. V., and 13 others. <strong>AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.</strong> Nature Genet. 42: 175-179, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081859</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081859[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081859">Louie et al. (2010)</a> identified a 2488C-T (arg830-to-trp; R830W) hypomorphic SNP in the WD40 repeat domain of the AHI1 gene that was associated with retinal degeneration in patients with nephronophthisis (NPHP; see, e.g., <a href="/entry/256100">256100</a>). Among 153 Italian NPHP individuals, the T allele was found at a higher frequency among those with retinal degeneration compared to those without retinal degeneration (25% compared to 1.8%, p = 5.36 x 10(-6)) and to controls, yielding a relative risk of 7.5. The findings were irrespective of the mutations causing NPHP, and suggested that variation in the AHI1 gene may explain some of the variability in retinal phenotypes. A similar association was not observed for 155 patients with Joubert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ingason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., and 29 others. <strong>A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.</strong> Hum. Molec. Genet. 19: 1379-1386, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20071346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20071346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20071346[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/10.1093/hmg/ddq009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20071346">Ingason et al. (2010)</a> noted that the AHI1 gene locus is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. <a href="#6" class="mim-tip-reference" title="Ingason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., and 29 others. <strong>A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.</strong> Hum. Molec. Genet. 19: 1379-1386, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20071346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20071346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20071346[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/10.1093/hmg/ddq009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20071346">Ingason et al. (2010)</a> replicated studies of AHI1 locus markers previously implicated in schizophrenia in a large European sample. Both the replication study and a metaanalysis showed evidence for significant overrepresentation of all tested alleles in patients compared with controls. They stated that the 6q23 region contains 2 other genes, C6orf217 and PDE7B (<a href="/entry/604645">604645</a>), that may be considered candidates for involvement in the genetic etiology of schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20071346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, <a href="#12" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified homozygosity for a nonsense and a missense mutation in the AHI1 gene in affected members of 2 families with Joubert syndrome-3 (<a href="#0008">608894.0008</a> and <a href="#0009">608894.0009</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> determined that 2 variants in the AHI1 gene resulting in truncated proteins at the C terminus and lacking the SH3 domain (c.3263delGG, <a href="#0004">608894.0004</a> and c.3196C-T) did not cause any abnormalities when expressed in zebrafish. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. In addition, <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> reported an unaffected member of a family segregating nonsyndromic hearing loss who carried the c.3196C-T variant in homozygosity. The findings indicated that the C-terminal SH3 domain of AHI1 is not required for normal development. <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> noted the implications for assessing variants in AHI1 that are part of preconception screening panels, and emphasized that even truncating variants identified in known disease genes must undergo stringent functional and segregation analysis before being classified as pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25616960" 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 the phylogenetic tree showing AHI1 gene evolution in hominoids, there was, as pointed out by <a href="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a>, evidence of a greater amount of protein change in the human lineage, suggesting a positive evolutionary selection. They suggested that changes in AHI1 may have been important in the evolution of human-specific motor behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" 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="#11" class="mim-tip-reference" title="Louie, C. M., Caridi, G., Lopes, V. S., Brancati, F., Kispert, A., Lancaster, M. A., Schlossman, A. M., Otto, E. A., Leitges, M., Grone, H.-J., Lopez, I., Gudiseva, H. V., and 13 others. <strong>AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.</strong> Nature Genet. 42: 175-179, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081859</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081859[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081859">Louie et al. (2010)</a> showed that Ahi1-null mice were runted and showed high mortality with grossly normal brain morphology. Histologic analysis of the retina showed rapid loss of the outer nuclear (photoreceptor) layer and complete absence of both rod and cone outer segments of photoreceptor cilia early postnatally. Apoptotic cell death was apparent by about 3 weeks of age. However, photoreceptor ciliary axonemes were intact and had normal 9 + 0 microtubule doublet configuration. In heterozygous control mice, Ahi1 expression was enriched at the connecting cilium and basal body and overlapped with expression of a Cetn2 (<a href="/entry/300006">300006</a>) transgene. These results indicated that absence of Ahi1 results in specific defects of outer segment morphogenesis and photoreceptor survival. The defects induced by Ahi1 loss were associated with misaccumulation of and mislocalization of opsin (<a href="/entry/180380">180380</a>), which contributed to the loss of photoreceptors. Mice doubly mutant for Nphp1 (<a href="/entry/607100">607100</a>) and Ahi1 showed a more severe phenotype, indicating a dosage-sensitive genetic interaction between Ahi1 and Nphp1 in retinal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Lancaster, M. A., Louie, C. M., Silhavy, J. L., Sintasath, L., DeCambre, M., Nigam, S. K., Willert, K., Gleeson, J. G. <strong>Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.</strong> Nature Med. 15: 1046-1054, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19718039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19718039">Lancaster et al. (2009)</a> found that surviving adult (5 months) Ahi1-null mice had smaller kidneys compared to wildtype and showed characteristics of nephronophthisis, including tubular basement membrane abnormalities, interstitial cell infiltrate and fibrosis, and appearance of multiple microcysts and tubular dilatation at about 1 year of age. Proximal tubules of the corticomedullary region were most affected. At 21 months of age, Ahi1-null mice showed renal impairment, with increased urinary protein content and defects in urine-concentrating abilities. However, renal ciliary formation and morphology were normal. Further studies indicated that loss of Ahi1 led to abrogation of basal Wnt (see, e.g., WNT3A; <a href="/entry/606359">606359</a>) activity in the adult mouse kidney. In vitro studies showed that the AHI1 protein acts as a positive modulator of the canonical WNT pathway, acting downstream of beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) stabilization. AHI1 was found to directly interact with and play a role in nuclear accumulation of beta-catenin. Ahi1-null mice showed defective repair of renal injury due to a defective WNT response, which resulted in cyst formation. The findings provided an explanation for the late onset of cyst formation, reflecting a gradual accumulation of mild damage and a defect in injury repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19718039" 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="Lancaster, M. A., Gopal, D. J., Kim, J., Saleem, S. N., Silhavy, J. L., Louie, C. M., Thacker, B. E., Williams, Y., Zaki, M. S., Gleeson, J. G. <strong>Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. (Letter)</strong> Nature Med. 17: 726-731, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21623382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21623382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21623382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21623382">Lancaster et al. (2011)</a> found that Ahi1-null mice had a hypoplastic cerebellum with an underdeveloped vermis and mildly defective foliation pattern, similar to that observed in Joubert syndrome. Vermian lobules VI and VII appeared fused, whereas lobule V appeared smaller and underdeveloped. Mutant mouse embryos showed a midline fusion defect with expansion of the rhombic roof plate. In wildtype mice, Ahi1 localized to the basal body in cerebellar granule neurons. Cerebellar granule neurons from mutant mice had normal numbers and morphology of cilia, suggesting that Ahi1 is not required for ciliogenesis, but rather functions in ciliary-mediated signaling. Accordingly, there was decreased Wnt activity at the site of hemisphere fusion, accompanied by reduced cellular proliferation at the site of fusion. Treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. The findings implicated a defect in Wnt signaling in the cerebellar midline phenotype that could be overcome with Wnt stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21623382" 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">rs121434348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434348;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=rs121434348" 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=rs121434348" 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 Saudi Arabian kindred, <a href="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> found that Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>) segregated with a homozygous nonsense mutation in the AHI1 gene: 1051C-T (arg351 to ter; R351X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434349 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434349;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/rs121434349?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=rs121434349" 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=rs121434349" 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 Saudi Arabian kindred, <a href="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> discovered that Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>) was associated with a homozygous 1303C-T transition in exon 7 of the AHI1 gene that resulted in an arg435-to-ter (R435X) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" 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">rs121434350 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434350;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=rs121434350" 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=rs121434350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Saudi Arabian kindred with Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), <a href="#4" class="mim-tip-reference" title="Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. <strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong> Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>] [<a href="https://doi.org/10.1038/ng1419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322546">Ferland et al. (2004)</a> found a homozygous 1328T-A transversion in exon 7 of the AHI1 gene, producing a nonconservative val443-to-asp (V443D) amino acid substitution, resulting in a change from a hydrophobic to a polar or charged residue. It was remarkable that 3 different mutations were found in Saudi Arabian pedigrees from the same geographic region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J. <strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong> J. Biol. Chem. 288: 13676-13694, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23532844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23532844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23532844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.420786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23532844">Tuz et al. (2013)</a> found that AHI1 with the V443D substitution failed to localize at cell-cell junctions and at the basal body of primary cilia when expressed in transfected IMCD3 mouse kidney cells. The mutation caused a slight, but significant, reduction in cilia formation, disrupted association of AHI1 with NPHP1 (<a href="/entry/607100">607100</a>) and HAP1 (<a href="/entry/600947">600947</a>), and caused AHI1 protein instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23532844" 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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AHI1, 2-BP DEL, 3263GG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906269;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs387906269</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906269 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906269;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=rs387906269" 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=rs387906269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled JOUBERT SYNDROME-3 based on the report of <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a>, has been reclassified based on the findings of <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25616960+16453322" 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 2 sibs (family MTI-229) with Joubert syndrome (<a href="/entry/608629">608629</a>), born of consanguineous Egyptian parents, <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a> identified a homozygous 2-bp deletion (3263delGG) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (fs1103X) in the SH3 domain. The mutation segregated with the disorder in the family. Both sibs had hypotonia, mental retardation, oculomotor apraxia, and retinitis pigmentosa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16453322" 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 another study of family MTI-229, <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> identified homozygosity for 2 mutations in the AHI1 gene: the c.3263delGG mutation (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906269;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs387906269</a>), resulting in a frameshift and premature termination (Trp1088LeufsTer16), as well as homozygosity for a ser761-to-leu (S761L; <a href="#0011">608894.0011</a>) substitution at a highly conserved residue in the fourth WD repeat domain. Expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish, suggesting that the S761L substitution is the causative mutation. <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> concluded that the C-terminal SH3 domain of AHI1 is not required for normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25616960" 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 with Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a> identified a homozygous 1765C-T transition in exon 13 of the AHI1 gene, resulting in an arg589-to-ter (R589X) substitution. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16453322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434351 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434351;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/rs121434351?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=rs121434351" 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=rs121434351" 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=RCV000002092 OR RCV000463110 OR RCV001172382 OR RCV001582460 OR RCV004752680" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002092, RCV000463110, RCV001172382, RCV001582460, RCV004752680" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002092...</a>
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<p>In a patient with Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), born of consanguineous Italian parents, <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a> identified a homozygous 2168G-A transition in exon 16 of the AHI1 gene, resulting in an arg723-to-gln (R723Q) substitution within a WD40 domain and predicted to disrupt salt bridging in this region. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16453322" 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>.0007 JOUBERT SYNDROME 3</strong>
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AHI1, 1-BP INS, 2369T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906270 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906270;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=rs387906270" 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=rs387906270" 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=RCV000002093" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002093" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002093</a>
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<p>In 2 Pakistani brothers with Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), born of consanguineous parents, <a href="#16" class="mim-tip-reference" title="Utsch, B., Sayer, J. A., Attanasio, M., Pereira, R. R., Eccles, M., Hennies, H.-C., Otto, E. A., Hildebrandt, F. <strong>Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome.</strong> Pediat. Nephrol. 21: 32-35, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240161</a>] [<a href="https://doi.org/10.1007/s00467-005-2054-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240161">Utsch et al. (2006)</a> identified a homozygous 1-bp insertion (2369insT) in exon 16 of the AHI1 gene, resulting in a frameshift and premature termination. Both boys had cerebellar ataxia, developmental delay, nystagmus, oculomotor apraxia. One developed end-stage renal failure by age 16 years due to nephronophthisis, thus expanding the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240161" 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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<strong>.0008 JOUBERT SYNDROME 3</strong>
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AHI1, ARG329TER
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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> rs201391050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201391050;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/rs201391050?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=rs201391050" 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=rs201391050" 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=RCV000023739 OR RCV000255060 OR RCV001074225 OR RCV001172379 OR RCV001390240" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023739, RCV000255060, RCV001074225, RCV001172379, RCV001390240" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023739...</a>
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<p>In a consanguineous family (8500306) in which 3 of 5 children had Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), characterized by moderate mental retardation, autism spectrum disorder, ataxia, and cerebellar atrophy, <a href="#12" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a homozygous G-to-A transition at genomic coordinate chr6:135820491 (NCBI36), resulting in an arg329-to-stop (R329X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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 JOUBERT SYNDROME 3</strong>
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AHI1, ARG495HIS
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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> rs387907003 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907003;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/rs387907003?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=rs387907003" 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=rs387907003" 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=RCV000023740 OR RCV002513203" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023740, RCV002513203" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023740...</a>
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<p>In a family (M332) in which 4 of 8 children of first-cousin parents had Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), characterized by severe mental retardation and cerebellar hypoplasia, <a href="#12" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a homozygous C-to-T transition at genomic coordinate chr6:135811263 (NCBI36), resulting in an arg495-to-his (R495H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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 JOUBERT SYNDROME 3</strong>
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AHI1, ARG351LEU
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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> rs397514726 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514726;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/rs397514726?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=rs397514726" 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=rs397514726" 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=RCV000054427" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054427" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054427</a>
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<p>In a daughter of first-cousin Middle Eastern parents, <a href="#15" class="mim-tip-reference" title="Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J. <strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong> J. Biol. Chem. 288: 13676-13694, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23532844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23532844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23532844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.420786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23532844">Tuz et al. (2013)</a> identified a homozygous G-to-T transversion at nucleotide 1052 of the AHI1 cDNA, resulting in an arg351-to-leu (R351L) substitution in the region between the coiled-coil domain and WD40 repeat domain of the AHI1 protein. The patient had developmental delay, ataxia, seizures, and classic brain image findings for Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>). When expressed in transfected IMCD3 mouse kidney cells, AHI1 with the R351L substitution failed to localize at cell-cell junctions and at the basal body of primary cilia. The mutation caused a slight, but significant, reduction in cilia formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23532844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 JOUBERT SYNDROME 3</strong>
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AHI1, SER761LEU
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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> rs794727174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727174;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/rs794727174?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=rs794727174" 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=rs794727174" 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=RCV000175088 OR RCV000185588 OR RCV001053820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000175088, RCV000185588, RCV001053820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000175088...</a>
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<p>In 2 sibs with Joubert syndrome-3 (JBTS3; <a href="/entry/608629">608629</a>), born of consanguineous Egyptian parents and originally reported by <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a>, <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> identified a homozygous mutation in exon 17 of the AHI1 gene, resulting in a ser761-to-leu (S761L) substitution at a highly conserved residue in the fourth WD repeat domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Sequencing Project, or Exome Aggregation Consortium databases, or in 1,629 in-house exomes. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25616960+16453322" 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 this family (family MTI-229), <a href="#17" class="mim-tip-reference" title="Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. <strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong> Ann. Neurol. 59: 527-534, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>] [<a href="https://doi.org/10.1002/ana.20749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16453322">Valente et al. (2006)</a> had previously identified a homozygous 2-bp deletion (c.3263delGG; <a href="#0004">608894.0004</a>) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (Trp1088LeufsTer16) in the SH3 domain. However, <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> determined that the c.3263delGG variant was not causative of the phenotype; expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. <a href="#3" class="mim-tip-reference" title="Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. <strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong> Hum. Molec. Genet. 24: 2594-2603, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[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/10.1093/hmg/ddv022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25616960">Elsayed et al. (2015)</a> concluded that the C-terminal SH3 domain of AHI1 is not required for normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25616960+16453322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/ncb2410" target="_blank">Full Text</a>]
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Dixon-Salazar, T., Silhavy, J. L., Marsh, S. E., Louie, C. M., Scott, L. C., Gururaj, A., Al-Gazali, L., Al-Tawari, A. A., Kayserili, H., Sztriha, L., Gleeson, J. G.
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<strong>Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467982[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467982" 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/10.1086/425985" target="_blank">Full Text</a>]
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Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others.
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<strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong>
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Hum. Molec. Genet. 24: 2594-2603, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25616960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25616960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25616960[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25616960" 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/ddv022" target="_blank">Full Text</a>]
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Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A.
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<strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong>
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Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1419" target="_blank">Full Text</a>]
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Hsiao, Y.-C., Tong, Z. J., Westfall, J. E., Ault, J. G., Page-McCaw, P. S., Ferland, R. J.
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<strong>Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.</strong>
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Hum. Molec. Genet. 18: 3926-3941, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625297[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625297" 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/ddp335" target="_blank">Full Text</a>]
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Ingason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., and 29 others.
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<strong>A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20071346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20071346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20071346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20071346" 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/ddq009" target="_blank">Full Text</a>]
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Jiang, X., Hanna, Z., Kaouass, M., Girard, L., Jolicoeur, P.
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<strong>Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12186888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12186888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12186888[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12186888" 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/10.1128/jvi.76.18.9046-9059.2002" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14751929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14751929</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14751929" 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/10.1182/blood-2003-11-4026" target="_blank">Full Text</a>]
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Lancaster, M. A., Gopal, D. J., Kim, J., Saleem, S. N., Silhavy, J. L., Louie, C. M., Thacker, B. E., Williams, Y., Zaki, M. S., Gleeson, J. G.
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<strong>Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21623382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21623382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21623382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21623382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm.2380" 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="10" class="mim-anchor"></a>
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<a id="Lancaster2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lancaster, M. A., Louie, C. M., Silhavy, J. L., Sintasath, L., DeCambre, M., Nigam, S. K., Willert, K., Gleeson, J. G.
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<strong>Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.</strong>
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Nature Med. 15: 1046-1054, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19718039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19718039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm.2010" 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="11" class="mim-anchor"></a>
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<a id="Louie2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Louie, C. M., Caridi, G., Lopes, V. S., Brancati, F., Kispert, A., Lancaster, M. A., Schlossman, A. M., Otto, E. A., Leitges, M., Grone, H.-J., Lopez, I., Gudiseva, H. V., and 13 others.
|
|
<strong>AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.</strong>
|
|
Nature Genet. 42: 175-179, 2010.
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|
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081859</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081859[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.519" 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="12" class="mim-anchor"></a>
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<a id="Najmabadi2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.
|
|
<strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong>
|
|
Nature 478: 57-63, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature10423" 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="13" class="mim-anchor"></a>
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<a id="Parisi2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Parisi, M. A., Doherty, D., Eckert, M. L., Shaw, D. W. W., Ozyurek, H., Aysun, S., Giray, O., Al Swaid, A., Al Shahwan, S., Dohayan, N., Bakhsh, E., Indridason, O. S., Dobyns, W. B., Bennett, C. L., Chance, P. F., Glass, I. A.
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|
<strong>AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.</strong>
|
|
J. Med. Genet. 43: 334-339, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155189</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155189[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16155189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.036608" 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="14" class="mim-anchor"></a>
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<a id="Sheng2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sheng, G., Xu, X., Lin, Y.-F., Wang, C.-E., Rong, J., Cheng, D., Peng, J., Jiang, X., Li, S.-H., Li, X.-J.
|
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<strong>Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.</strong>
|
|
J. Clin. Invest. 118: 2785-2795, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18636121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18636121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18636121[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18636121" 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/10.1172/JCI35339" 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="15" class="mim-anchor"></a>
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<a id="Tuz2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J.
|
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<strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong>
|
|
J. Biol. Chem. 288: 13676-13694, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23532844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23532844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23532844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23532844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M112.420786" 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="16" class="mim-anchor"></a>
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<a id="Utsch2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Utsch, B., Sayer, J. A., Attanasio, M., Pereira, R. R., Eccles, M., Hennies, H.-C., Otto, E. A., Hildebrandt, F.
|
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<strong>Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome.</strong>
|
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Pediat. Nephrol. 21: 32-35, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240161</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00467-005-2054-y" 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="17" class="mim-anchor"></a>
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<a id="Valente2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others.
|
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<strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong>
|
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Ann. Neurol. 59: 527-534, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16453322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16453322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16453322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20749" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/29/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 8/6/2013<br>Patricia A. Hartz - updated : 11/27/2012<br>Ada Hamosh - updated : 1/6/2012<br>George E. Tiller - updated : 11/8/2011<br>Cassandra L. Kniffin - updated : 9/6/2011<br>George E. Tiller - updated : 8/6/2010<br>Cassandra L. Kniffin - updated : 4/8/2010<br>Cassandra L. Kniffin - updated : 2/24/2010<br>Patricia A. Hartz - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 11/2/2007<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Marla J. F. O'Neill - updated : 7/6/2006<br>Victor A. McKusick - updated : 11/11/2004<br>Victor A. McKusick - updated : 9/10/2004
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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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Patricia A. Hartz : 9/1/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/01/2024
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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 : 07/28/2021<br>alopez : 10/04/2016<br>carol : 07/06/2015<br>mcolton : 6/30/2015<br>ckniffin : 6/29/2015<br>carol : 9/25/2013<br>carol : 8/14/2013<br>mgross : 8/6/2013<br>alopez : 1/30/2013<br>terry : 11/28/2012<br>alopez : 11/27/2012<br>terry : 11/27/2012<br>carol : 1/6/2012<br>terry : 1/6/2012<br>carol : 11/8/2011<br>terry : 11/8/2011<br>carol : 9/7/2011<br>ckniffin : 9/6/2011<br>wwang : 8/10/2010<br>terry : 8/6/2010<br>wwang : 4/13/2010<br>ckniffin : 4/8/2010<br>alopez : 3/3/2010<br>alopez : 3/3/2010<br>ckniffin : 2/24/2010<br>mgross : 3/24/2009<br>terry : 3/23/2009<br>wwang : 11/13/2007<br>ckniffin : 11/2/2007<br>wwang : 8/16/2007<br>ckniffin : 8/3/2007<br>wwang : 7/6/2006<br>alopez : 7/14/2005<br>tkritzer : 11/15/2004<br>tkritzer : 11/12/2004<br>terry : 11/11/2004<br>alopez : 9/24/2004<br>alopez : 9/24/2004<br>alopez : 9/15/2004<br>terry : 9/10/2004<br>mgross : 9/1/2004<br>mgross : 9/1/2004
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608894
|
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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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|
ABELSON HELPER INTEGRATION SITE 1; AHI1
|
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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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JOUBERIN
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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: AHI1</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: 6q23.3
|
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:135,283,532-135,497,740 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<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>
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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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6q23.3
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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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Joubert syndrome 3
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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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608629
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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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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>AHI1 is a component of a protein complex in the basal body, a ring-like structure that functions in the transition zone at the base of cilia. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (Chih et al., 2012). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By searching databases for sequences similar to mouse and rat Ahi1, Jiang et al. (2002) identified 3 splice variants of human AHI1. Full-length human AHI1 contains at least 1,187 amino acids. Both the rodent and human proteins have 7 WD40 repeats and an SH3 domain, but human AHI1 contains an N-terminal coiled-coil domain not found in the rodent proteins. One of the human AHI1 splice variants encodes a protein lacking the SH3 domain. RT-PCR analysis of Jurkat human T cells identified splice variants exhibiting exon skipping in the 5-prime UTR. Northern blot analysis of mouse tissues detected several Ahi1 splice variants, with highest expression in brain and testis and very low expression in liver. </p><p>Ferland et al. (2004) noted that the AHI1 gene contains a coiled-coil domain in its N-terminal 140 amino acids. These amino acids and this domain are entirely missing in the predicted proteins of both mouse and rat, but are present in the predicted proteins of nonhuman primates and other mammals (cow, pig, dog, and cat). </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>Jiang et al. (2004) found that expression of mouse and human AHI1 was highest in the most primitive types of normal hematopoietic cells and was downregulated during early differentiation. Cells from 28 patients with chronic myeloid leukemia (CML; 608232) showed elevated AHI1 mRNA in all disease phases and at all stages of differentiation, including quiescent CD34 (142230)-positive cells and terminally differentiating cells. In the most primitive CML cells, transcripts of the 2 shorter isoforms of AHI1 were also increased. Although 15 of 16 human lymphoid and myeloid leukemic cell lines showed aberrant control of AHI1 expression, this was not seen in blasts obtained directly from 15 patients with acute Philadelphia chromosome-negative leukemia. Jiang et al. (2004) concluded that downregulation of AHI1 expression is a conserved step in primitive normal hematopoietic cell differentiation and that perturbations in AHI1 expression may contribute to the development of specific types of human leukemia. </p><p>Using immunoprecipitation analysis, Sheng et al. (2008) found that Ahi1 bound tightly to Hap1 (600947) in mouse brain lysates. Depletion of either protein reduced the amount of the other, and conversely, overexpression of either protein increased the endogenous level of the other, suggesting Ahi1 and Hap1 stabilize each other. Reduction of either Hap1 or Ahi1 also reduced the level of Trkb (NTRK2; 600456) and Trkb signaling, as indicated by reduced phosphorylation of Erk (see 601795) and Akt (see 164730). Sheng et al. (2008) concluded that HAP1 and AHI1 maintain the level and signaling of TRKB in neurons. </p><p>Hsiao et al. (2009) showed that AHI1 regulated formation of the primary nonmotile cilium via its interaction with RAB8A (165040), a small GTPase critical for polarized membrane trafficking. Mouse Ahi1 protein localized to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In mice, RNAi knockdown of Ahi1 expression led to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a was destabilized and did not properly localize to the basal body. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. Hsiao et al. (2009) concluded that the distribution and functioning of RAB8A is regulated by AHI1, not only affecting cilium formation, but also vesicle transport. </p><p>Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (614144) in mouse IMCD3 cells and embryonic fibroblasts, Chih et al. (2012) identified several components of the B9d1-containing ciliary complex, including Tmem231 (614949), Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1 (609883), Ahi1, Cc2d2a (612013), and Kctd10 (613421). </p><p>By coimmunoprecipitation of transfected HEK293 cells, Tuz et al. (2013) found that AHI1 interacted with NPHP1 (607100) and with HAP1. Gel filtration followed by Western blot analysis confirmed the interactions and suggested that AHI1 and NPHP1 form heterodimers of about 210 kD and heterotetramers of about 430 kD. AHI1 formed 470-kD heterotetramers, but not heterodimers, with HAP1. Tuz et al. (2013) reported that the WD40 repeats of AHI1 interacted with the SH3 domain of NPHP1, and they found that the region between the coiled-coil domain and central WD40 repeat domain of AHI1 bound the N-terminal TATA-binding protein-interacting region of HAP1. Western blot and immunohistochemical analyses of Ahi1 -/- mouse brain showed that loss of Ahi1 reduced Hap1 content overall and eliminated Hap1 staining in the stigmoid body of hypothalamus. </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>Jiang et al. (2002) determined that the AHI1 gene contains at least 33 exons and spans 213.7 kb. The protein-coding sequence begins in exon 4. </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>Ferland et al. (2004) identified the AHI1 gene within a locus on chromosome 6q23.2-q23.3 to which Joubert syndrome (608629) had been mapped. </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>Ferland et al. (2004) carried out a genomewide screen in 3 Saudi Arabian pedigrees from the same geographic region with autosomal recessive Joubert syndrome-3 (JBTS3; 608629). The addition of another Saudi Arabian family and a pedigree from Turkey narrowed the region of shared homozygosity. Pooling of linkage data and lod scores from the 5 pedigrees resulted in a summed multipoint lod score of 8.36 and a maximum 2-point lod score of 6.31 (at recombination fraction = 0.0) at marker D6S1626. Sequencing of candidate genes in the minimal region of linkage identified 3 independent mutations in the AHI1 gene (608894.0001-608894.0003). It is remarkable that Ferland et al. (2004) found homozygosity for 3 different mutations in the AHI1 gene in the 3 Saudi Arabian families living in the same geographic region. No mutation was identified in the Saudi Arabian family from another region or in the Turkish pedigree. </p><p>In affected members of 3 consanguineous families with Joubert syndrome, some with cortical polymicrogyria, Dixon-Salazar et al. (2004) identified 1 missense and 2 frameshift mutations in the AHI1 gene. They designated the AHI1 protein Jouberin. The gene is expressed strongly in embryonic hindbrain and forebrain, and the data of Dixon-Salazar et al. (2004) suggested that AHI1 is required for both cerebellar and cortical development in humans. The authors pointed out that in a subset of patients with Joubert syndrome plus nephronophthisis, the phenotype is caused by mutation in the NPHP1 gene (607100.0005). Nephrocystin, the protein encoded by NPHP1, contains an SH3 domain, suggesting that a shared pathway may be involved in these different forms of Joubert syndrome. </p><p>Using a combination of haplotype analysis and gene sequencing, Parisi et al. (2006) screened 117 probands with Joubert syndrome for mutations in the AHI1 gene and identified a total of 15 novel and 5 previously identified mutations in 19 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Fourteen of the mutation-positive families were consanguineous, but no single founder mutation was apparent. </p><p>Valente et al. (2006) identified 15 different mutations (see, e.g., 608894.0004-608894.0006) in the AHI1 gene in 11 patients from 10 families with Joubert syndrome. These patients accounted for 7.3% of 137 probands with the molar tooth sign and Joubert-related disorders. A phenotype-specific group of Joubert plus retinopathy had an AHI1 mutation frequency of 21.7% (5 of 23 probands). Clinical analysis indicated that AHI1 mutations were not associated with kidney or liver changes. Retinal abnormalities ranged from retinitis pigmentosa to blindness. There were 2 splice site mutations, 1 missense, and 12 truncating mutations, of which 11 were predicted to abolish all of the SH3 domain and all or part of the WD40 domain. In 2 Egyptian sibs (family MTI-229) with Joubert syndrome-3 originally reported by Valente et al. (2006), Elsayed et al. (2015) found that the causative AHI1 mutation was a homozygous missense change (S761L; 608894.0011) rather than a C-terminal deletion (c.3263delGG; 608894.0004). The missense mutation was found by homozygosity mapping and whole-exome sequencing. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. Expression of the c.3263delGG mutation in zebrafish did not cause any abnormalities, suggesting that the C-terminal SH3 domain of AHI1 is not required for normal development. </p><p>Louie et al. (2010) identified a 2488C-T (arg830-to-trp; R830W) hypomorphic SNP in the WD40 repeat domain of the AHI1 gene that was associated with retinal degeneration in patients with nephronophthisis (NPHP; see, e.g., 256100). Among 153 Italian NPHP individuals, the T allele was found at a higher frequency among those with retinal degeneration compared to those without retinal degeneration (25% compared to 1.8%, p = 5.36 x 10(-6)) and to controls, yielding a relative risk of 7.5. The findings were irrespective of the mutations causing NPHP, and suggested that variation in the AHI1 gene may explain some of the variability in retinal phenotypes. A similar association was not observed for 155 patients with Joubert syndrome. </p><p>Ingason et al. (2010) noted that the AHI1 gene locus is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Ingason et al. (2010) replicated studies of AHI1 locus markers previously implicated in schizophrenia in a large European sample. Both the replication study and a metaanalysis showed evidence for significant overrepresentation of all tested alleles in patients compared with controls. They stated that the 6q23 region contains 2 other genes, C6orf217 and PDE7B (604645), that may be considered candidates for involvement in the genetic etiology of schizophrenia. </p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a nonsense and a missense mutation in the AHI1 gene in affected members of 2 families with Joubert syndrome-3 (608894.0008 and 608894.0009, respectively). </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>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Elsayed et al. (2015) determined that 2 variants in the AHI1 gene resulting in truncated proteins at the C terminus and lacking the SH3 domain (c.3263delGG, 608894.0004 and c.3196C-T) did not cause any abnormalities when expressed in zebrafish. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. In addition, Elsayed et al. (2015) reported an unaffected member of a family segregating nonsyndromic hearing loss who carried the c.3196C-T variant in homozygosity. The findings indicated that the C-terminal SH3 domain of AHI1 is not required for normal development. Elsayed et al. (2015) noted the implications for assessing variants in AHI1 that are part of preconception screening panels, and emphasized that even truncating variants identified in known disease genes must undergo stringent functional and segregation analysis before being classified as pathogenic. </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>Evolution</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 the phylogenetic tree showing AHI1 gene evolution in hominoids, there was, as pointed out by Ferland et al. (2004), evidence of a greater amount of protein change in the human lineage, suggesting a positive evolutionary selection. They suggested that changes in AHI1 may have been important in the evolution of human-specific motor behaviors. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Louie et al. (2010) showed that Ahi1-null mice were runted and showed high mortality with grossly normal brain morphology. Histologic analysis of the retina showed rapid loss of the outer nuclear (photoreceptor) layer and complete absence of both rod and cone outer segments of photoreceptor cilia early postnatally. Apoptotic cell death was apparent by about 3 weeks of age. However, photoreceptor ciliary axonemes were intact and had normal 9 + 0 microtubule doublet configuration. In heterozygous control mice, Ahi1 expression was enriched at the connecting cilium and basal body and overlapped with expression of a Cetn2 (300006) transgene. These results indicated that absence of Ahi1 results in specific defects of outer segment morphogenesis and photoreceptor survival. The defects induced by Ahi1 loss were associated with misaccumulation of and mislocalization of opsin (180380), which contributed to the loss of photoreceptors. Mice doubly mutant for Nphp1 (607100) and Ahi1 showed a more severe phenotype, indicating a dosage-sensitive genetic interaction between Ahi1 and Nphp1 in retinal development. </p><p>Lancaster et al. (2009) found that surviving adult (5 months) Ahi1-null mice had smaller kidneys compared to wildtype and showed characteristics of nephronophthisis, including tubular basement membrane abnormalities, interstitial cell infiltrate and fibrosis, and appearance of multiple microcysts and tubular dilatation at about 1 year of age. Proximal tubules of the corticomedullary region were most affected. At 21 months of age, Ahi1-null mice showed renal impairment, with increased urinary protein content and defects in urine-concentrating abilities. However, renal ciliary formation and morphology were normal. Further studies indicated that loss of Ahi1 led to abrogation of basal Wnt (see, e.g., WNT3A; 606359) activity in the adult mouse kidney. In vitro studies showed that the AHI1 protein acts as a positive modulator of the canonical WNT pathway, acting downstream of beta-catenin (CTNNB1; 116806) stabilization. AHI1 was found to directly interact with and play a role in nuclear accumulation of beta-catenin. Ahi1-null mice showed defective repair of renal injury due to a defective WNT response, which resulted in cyst formation. The findings provided an explanation for the late onset of cyst formation, reflecting a gradual accumulation of mild damage and a defect in injury repair. </p><p>Lancaster et al. (2011) found that Ahi1-null mice had a hypoplastic cerebellum with an underdeveloped vermis and mildly defective foliation pattern, similar to that observed in Joubert syndrome. Vermian lobules VI and VII appeared fused, whereas lobule V appeared smaller and underdeveloped. Mutant mouse embryos showed a midline fusion defect with expansion of the rhombic roof plate. In wildtype mice, Ahi1 localized to the basal body in cerebellar granule neurons. Cerebellar granule neurons from mutant mice had normal numbers and morphology of cilia, suggesting that Ahi1 is not required for ciliogenesis, but rather functions in ciliary-mediated signaling. Accordingly, there was decreased Wnt activity at the site of hemisphere fusion, accompanied by reduced cellular proliferation at the site of fusion. Treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. The findings implicated a defect in Wnt signaling in the cerebellar midline phenotype that could be overcome with Wnt stimulation. </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>11 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 JOUBERT SYNDROME 3</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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AHI1, ARG351TER
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<br />
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SNP: rs121434348,
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ClinVar: RCV000002087, RCV001058641
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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 Saudi Arabian kindred, Ferland et al. (2004) found that Joubert syndrome-3 (JBTS3; 608629) segregated with a homozygous nonsense mutation in the AHI1 gene: 1051C-T (arg351 to ter; R351X). </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 JOUBERT SYNDROME 3</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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AHI1, ARG435TER
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<br />
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SNP: rs121434349,
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gnomAD: rs121434349,
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ClinVar: RCV000002088, RCV003495105
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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 Saudi Arabian kindred, Ferland et al. (2004) discovered that Joubert syndrome-3 (JBTS3; 608629) was associated with a homozygous 1303C-T transition in exon 7 of the AHI1 gene that resulted in an arg435-to-ter (R435X) mutation. </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>.0003 JOUBERT SYNDROME 3</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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AHI1, VAL443ASP
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<br />
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SNP: rs121434350,
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ClinVar: RCV000002089, RCV000162132
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Saudi Arabian kindred with Joubert syndrome-3 (JBTS3; 608629), Ferland et al. (2004) found a homozygous 1328T-A transversion in exon 7 of the AHI1 gene, producing a nonconservative val443-to-asp (V443D) amino acid substitution, resulting in a change from a hydrophobic to a polar or charged residue. It was remarkable that 3 different mutations were found in Saudi Arabian pedigrees from the same geographic region. </p><p>Tuz et al. (2013) found that AHI1 with the V443D substitution failed to localize at cell-cell junctions and at the basal body of primary cilia when expressed in transfected IMCD3 mouse kidney cells. The mutation caused a slight, but significant, reduction in cilia formation, disrupted association of AHI1 with NPHP1 (607100) and HAP1 (600947), and caused AHI1 protein instability. </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>.0004 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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AHI1, 2-BP DEL, 3263GG ({dbSNP rs387906269})
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<br />
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SNP: rs387906269,
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ClinVar: RCV000002090
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>This variant, formerly titled JOUBERT SYNDROME-3 based on the report of Valente et al. (2006), has been reclassified based on the findings of Elsayed et al. (2015). </p><p>In 2 sibs (family MTI-229) with Joubert syndrome (608629), born of consanguineous Egyptian parents, Valente et al. (2006) identified a homozygous 2-bp deletion (3263delGG) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (fs1103X) in the SH3 domain. The mutation segregated with the disorder in the family. Both sibs had hypotonia, mental retardation, oculomotor apraxia, and retinitis pigmentosa. </p><p>In another study of family MTI-229, Elsayed et al. (2015) identified homozygosity for 2 mutations in the AHI1 gene: the c.3263delGG mutation (rs387906269), resulting in a frameshift and premature termination (Trp1088LeufsTer16), as well as homozygosity for a ser761-to-leu (S761L; 608894.0011) substitution at a highly conserved residue in the fourth WD repeat domain. Expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish, suggesting that the S761L substitution is the causative mutation. Elsayed et al. (2015) concluded that the C-terminal SH3 domain of AHI1 is not required for normal development. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 JOUBERT SYNDROME 3</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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AHI1, ARG589TER,
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<br />
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SNP: rs267606641,
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gnomAD: rs267606641,
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ClinVar: RCV000002091, RCV000522479, RCV001376341, RCV001380010
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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 with Joubert syndrome-3 (JBTS3; 608629), Valente et al. (2006) identified a homozygous 1765C-T transition in exon 13 of the AHI1 gene, resulting in an arg589-to-ter (R589X) substitution. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa. </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 JOUBERT SYNDROME 3</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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AHI1, ARG723GLN
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<br />
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|
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SNP: rs121434351,
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gnomAD: rs121434351,
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ClinVar: RCV000002092, RCV000463110, RCV001172382, RCV001582460, RCV004752680
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous Italian parents, Valente et al. (2006) identified a homozygous 2168G-A transition in exon 16 of the AHI1 gene, resulting in an arg723-to-gln (R723Q) substitution within a WD40 domain and predicted to disrupt salt bridging in this region. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 JOUBERT SYNDROME 3</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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AHI1, 1-BP INS, 2369T
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<br />
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SNP: rs387906270,
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ClinVar: RCV000002093
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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 2 Pakistani brothers with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous parents, Utsch et al. (2006) identified a homozygous 1-bp insertion (2369insT) in exon 16 of the AHI1 gene, resulting in a frameshift and premature termination. Both boys had cerebellar ataxia, developmental delay, nystagmus, oculomotor apraxia. One developed end-stage renal failure by age 16 years due to nephronophthisis, thus expanding the clinical phenotype. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 JOUBERT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
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AHI1, ARG329TER
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|
|
|
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<br />
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|
|
SNP: rs201391050,
|
|
|
|
|
|
gnomAD: rs201391050,
|
|
|
|
|
|
ClinVar: RCV000023739, RCV000255060, RCV001074225, RCV001172379, RCV001390240
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous family (8500306) in which 3 of 5 children had Joubert syndrome-3 (JBTS3; 608629), characterized by moderate mental retardation, autism spectrum disorder, ataxia, and cerebellar atrophy, Najmabadi et al. (2011) identified a homozygous G-to-A transition at genomic coordinate chr6:135820491 (NCBI36), resulting in an arg329-to-stop (R329X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 JOUBERT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AHI1, ARG495HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907003,
|
|
|
|
|
|
gnomAD: rs387907003,
|
|
|
|
|
|
ClinVar: RCV000023740, RCV002513203
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (M332) in which 4 of 8 children of first-cousin parents had Joubert syndrome-3 (JBTS3; 608629), characterized by severe mental retardation and cerebellar hypoplasia, Najmabadi et al. (2011) identified a homozygous C-to-T transition at genomic coordinate chr6:135811263 (NCBI36), resulting in an arg495-to-his (R495H) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 JOUBERT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AHI1, ARG351LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514726,
|
|
|
|
|
|
gnomAD: rs397514726,
|
|
|
|
|
|
ClinVar: RCV000054427
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a daughter of first-cousin Middle Eastern parents, Tuz et al. (2013) identified a homozygous G-to-T transversion at nucleotide 1052 of the AHI1 cDNA, resulting in an arg351-to-leu (R351L) substitution in the region between the coiled-coil domain and WD40 repeat domain of the AHI1 protein. The patient had developmental delay, ataxia, seizures, and classic brain image findings for Joubert syndrome-3 (JBTS3; 608629). When expressed in transfected IMCD3 mouse kidney cells, AHI1 with the R351L substitution failed to localize at cell-cell junctions and at the basal body of primary cilia. The mutation caused a slight, but significant, reduction in cilia formation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 JOUBERT SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AHI1, SER761LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs794727174,
|
|
|
|
|
|
gnomAD: rs794727174,
|
|
|
|
|
|
ClinVar: RCV000175088, RCV000185588, RCV001053820
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous Egyptian parents and originally reported by Valente et al. (2006), Elsayed et al. (2015) identified a homozygous mutation in exon 17 of the AHI1 gene, resulting in a ser761-to-leu (S761L) substitution at a highly conserved residue in the fourth WD repeat domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Sequencing Project, or Exome Aggregation Consortium databases, or in 1,629 in-house exomes. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. </p><p>In this family (family MTI-229), Valente et al. (2006) had previously identified a homozygous 2-bp deletion (c.3263delGG; 608894.0004) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (Trp1088LeufsTer16) in the SH3 domain. However, Elsayed et al. (2015) determined that the c.3263delGG variant was not causative of the phenotype; expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. Elsayed et al. (2015) concluded that the C-terminal SH3 domain of AHI1 is not required for normal development. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
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|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S.
|
|
<strong>A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.</strong>
|
|
Nature Cell Biol. 14: 61-72, 2012.
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[PubMed: 22179047]
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[Full Text: https://doi.org/10.1038/ncb2410]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Dixon-Salazar, T., Silhavy, J. L., Marsh, S. E., Louie, C. M., Scott, L. C., Gururaj, A., Al-Gazali, L., Al-Tawari, A. A., Kayserili, H., Sztriha, L., Gleeson, J. G.
|
|
<strong>Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria.</strong>
|
|
Am. J. Hum. Genet. 75: 979-987, 2004.
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|
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|
[PubMed: 15467982]
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[Full Text: https://doi.org/10.1086/425985]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others.
|
|
<strong>Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene.</strong>
|
|
Hum. Molec. Genet. 24: 2594-2603, 2015.
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[PubMed: 25616960]
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[Full Text: https://doi.org/10.1093/hmg/ddv022]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A.
|
|
<strong>Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.</strong>
|
|
Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004.
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|
|
[PubMed: 15322546]
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|
[Full Text: https://doi.org/10.1038/ng1419]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Hsiao, Y.-C., Tong, Z. J., Westfall, J. E., Ault, J. G., Page-McCaw, P. S., Ferland, R. J.
|
|
<strong>Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.</strong>
|
|
Hum. Molec. Genet. 18: 3926-3941, 2009.
|
|
|
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|
|
[PubMed: 19625297]
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[Full Text: https://doi.org/10.1093/hmg/ddp335]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ingason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., and 29 others.
|
|
<strong>A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.</strong>
|
|
Hum. Molec. Genet. 19: 1379-1386, 2010.
|
|
|
|
|
|
[PubMed: 20071346]
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|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddq009]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Jiang, X., Hanna, Z., Kaouass, M., Girard, L., Jolicoeur, P.
|
|
<strong>Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations.</strong>
|
|
J. Virol. 76: 9046-9059, 2002.
|
|
|
|
|
|
[PubMed: 12186888]
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|
|
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|
|
[Full Text: https://doi.org/10.1128/jvi.76.18.9046-9059.2002]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Jiang, X., Zhao, Y., Chan, W.-Y., Vercauteren, S., Pang, E., Kennedy, S., Nicolini, F., Eaves, A., Eaves, C.
|
|
<strong>Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia.</strong>
|
|
Blood 103: 3897-3904, 2004.
|
|
|
|
|
|
[PubMed: 14751929]
|
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|
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|
|
[Full Text: https://doi.org/10.1182/blood-2003-11-4026]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lancaster, M. A., Gopal, D. J., Kim, J., Saleem, S. N., Silhavy, J. L., Louie, C. M., Thacker, B. E., Williams, Y., Zaki, M. S., Gleeson, J. G.
|
|
<strong>Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. (Letter)</strong>
|
|
Nature Med. 17: 726-731, 2011.
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|
|
|
|
[PubMed: 21623382]
|
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|
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|
|
[Full Text: https://doi.org/10.1038/nm.2380]
|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Lancaster, M. A., Louie, C. M., Silhavy, J. L., Sintasath, L., DeCambre, M., Nigam, S. K., Willert, K., Gleeson, J. G.
|
|
<strong>Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.</strong>
|
|
Nature Med. 15: 1046-1054, 2009.
|
|
|
|
|
|
[PubMed: 19718039]
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[Full Text: https://doi.org/10.1038/nm.2010]
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Louie, C. M., Caridi, G., Lopes, V. S., Brancati, F., Kispert, A., Lancaster, M. A., Schlossman, A. M., Otto, E. A., Leitges, M., Grone, H.-J., Lopez, I., Gudiseva, H. V., and 13 others.
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<strong>AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.</strong>
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Nature Genet. 42: 175-179, 2010.
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[PubMed: 20081859]
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[Full Text: https://doi.org/10.1038/ng.519]
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Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.
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<strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong>
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Nature 478: 57-63, 2011.
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[PubMed: 21937992]
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[Full Text: https://doi.org/10.1038/nature10423]
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Parisi, M. A., Doherty, D., Eckert, M. L., Shaw, D. W. W., Ozyurek, H., Aysun, S., Giray, O., Al Swaid, A., Al Shahwan, S., Dohayan, N., Bakhsh, E., Indridason, O. S., Dobyns, W. B., Bennett, C. L., Chance, P. F., Glass, I. A.
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<strong>AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.</strong>
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J. Med. Genet. 43: 334-339, 2006.
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[PubMed: 16155189]
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[Full Text: https://doi.org/10.1136/jmg.2005.036608]
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Sheng, G., Xu, X., Lin, Y.-F., Wang, C.-E., Rong, J., Cheng, D., Peng, J., Jiang, X., Li, S.-H., Li, X.-J.
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<strong>Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.</strong>
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J. Clin. Invest. 118: 2785-2795, 2008.
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[PubMed: 18636121]
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[Full Text: https://doi.org/10.1172/JCI35339]
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Tuz, K., Hsiao, Y.-C., Juarez, O., Shi, B., Harmon, E. Y., Phelps, I. G., Lennartz, M. R., Glass, I. A., Doherty, D., Ferland, R. J.
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<strong>The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions.</strong>
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J. Biol. Chem. 288: 13676-13694, 2013.
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[PubMed: 23532844]
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[Full Text: https://doi.org/10.1074/jbc.M112.420786]
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Utsch, B., Sayer, J. A., Attanasio, M., Pereira, R. R., Eccles, M., Hennies, H.-C., Otto, E. A., Hildebrandt, F.
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<strong>Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome.</strong>
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Pediat. Nephrol. 21: 32-35, 2006.
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[PubMed: 16240161]
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[Full Text: https://doi.org/10.1007/s00467-005-2054-y]
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Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others.
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<strong>AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.</strong>
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Ann. Neurol. 59: 527-534, 2006.
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[PubMed: 16453322]
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[Full Text: https://doi.org/10.1002/ana.20749]
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Cassandra L. Kniffin - updated : 6/29/2015<br>Patricia A. Hartz - updated : 8/6/2013<br>Patricia A. Hartz - updated : 11/27/2012<br>Ada Hamosh - updated : 1/6/2012<br>George E. Tiller - updated : 11/8/2011<br>Cassandra L. Kniffin - updated : 9/6/2011<br>George E. Tiller - updated : 8/6/2010<br>Cassandra L. Kniffin - updated : 4/8/2010<br>Cassandra L. Kniffin - updated : 2/24/2010<br>Patricia A. Hartz - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 11/2/2007<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Marla J. F. O'Neill - updated : 7/6/2006<br>Victor A. McKusick - updated : 11/11/2004<br>Victor A. McKusick - updated : 9/10/2004
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Patricia A. Hartz : 9/1/2004
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